Electrospray coating of objects

ABSTRACT

Electrospray methods and systems for coating of objects (e.g., medical devices such as a stent structure) with selected types of coatings (e.g., open matrix coating and closed film coating)

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/764,229 filed 31 Jan. 2006, entitled “Electrospraying apparatusand method for coating objects,” which is incorporated herein byreference in its entirety.

STATEMENT OF GOVERNMENT RIGHTS

The present invention was made with support from the National ScienceFoundation (NSF) under Grant No. 0512496. The government may havecertain rights in this invention.

BACKGROUND OF THE INVENTION

The present invention relates to coating objects, and more particularly,the present invention relates to coating objects (e.g., medical devices)using electrospray technology.

It is often beneficial to coat objects (e.g., medical devices) so thatthe surfaces of such devices have desired properties or provide desiredeffects. For example, it is useful to coat medical devices to providefor the localized delivery of therapeutic agents to target locationswithin the body, such as to treat localized disease (e.g., heartdisease) or occluded body lumens. Local drug delivery may be achieved,for example, by coating balloon catheters, stents, and the like withtherapeutic agent to be locally delivered. The coating of medicaldevices may provide for controlled release, which includes long-term orsustained release, of a bioactive material.

Aside from facilitating localized drug delivery, medical devices arecoated with materials to provide beneficial surface properties. Forexample, medical devices are often coated with radiopaque materials toallow for fluoroscopic visualization during placement in the body. It isalso useful to coat certain devices to achieve enhanced biocompatibilityand to improve surface properties such as lubriciousness.

Further, for example, it is often beneficial to coat stents, e.g., forthe controlled release of pharmacological agents, surface propertycontrol and effects, etc. Stents are implanted within vessels in aneffort to maintain the patency thereof by preventing collapse and/orimpeding restenosis. For example, implantation of a stent may beaccomplished by mounting the stent on the expandable portion of aballoon catheter, maneuvering the catheter through the vasculature so asto position the stent at the treatment site within the body lumen, andinflating the balloon to expand the stent so as to engage the lumenwall. The stent deforms in the expanded configuration allowing theballoon to be deflated and the catheter removed to complete theimplantation procedure. Further, for example, the use of self-expandingstents obviates the need for a balloon delivery device. Instead, aconstraining sheath that is initially fitted above the stent is simplyretracted once the stent is in position adjacent the treatment site.Stents and stent delivery catheters are well known in the art and thevarious configurations thereof makes it impossible to describe each andevery stent structure or related materials.

The success of a stent placement can be assessed by evaluating a numberof factors, such as thrombosis, neointimal hyperplasia, smooth musclecell migration, and proliferation following implantation of the stent,injury to the artery wall, overall loss of lumenal patency, stentdiameter in vivo, thickness of the stent, and leukocyte adhesion to thelumenal lining of stented arteries. The chief areas of concern are earlysubacute thrombosis and eventual restenosis of the blood vessel due tointimal hyperplasia.

Therapeutic pharmacological agents have been developed to address someof the concerns associated with the placement of the stent. It is oftendesirable to provide localized pharmacological treatment of the vesselat the site being supported by the stent. As it would be convenient toutilize the implanted stent for such purpose, the stent may serve bothas a support for a lumenal wall as well as a delivery vehicle for thepharmacological agent.

Conventionally, coatings have been applied to objects such as medicaldevices, including stents, by processes such as dipping, spraying, vapordeposition, plasma polymerization, as wells as electroplating andelectrostatic deposition. Although many of these processes have beenused to produce satisfactory coatings, there are numerous potentialdrawbacks associated therewith.

For example, it is often difficult to achieve coatings of uniformthicknesses, both on the individual parts and on batches of parts. Also,many coating materials are otherwise difficult to use, such as thosethat are incompatible, insoluble, unsuspendable, or that are unstablecoating solutions.

Further, for example, many coating processes result in coatings that donot provide a uniform drug dose per medical device. Further, suchconventional methods have generally failed to provide a quick, easy, andinexpensive way of providing drugs onto a stent. For example,deficiencies of such conventional methods are, at least in part, relatedto the control of the coating process (e.g., the ability to control thecoating uniformity and thickness, the ability to control the size ofparticles used to coat the device, the control of the coating so as tocontrol the rate of the release of the drug upon implantation of thestent, etc.). Likewise, in many processes, the coating materials arefairly costly, and in many coating processes such coating materials arewasted due to the type of coating methods being used.

Therefore, the need for an effective method and system of coatingobjects such as medical devices exists.

SUMMARY OF THE INVENTION

The methods and systems according to the present invention provide forthe coating of objects (e.g., coating of medical devices such as stentsand catheters, depositing film on any object for texturing the surfacethereof, providing a protective layer on an object, constructing anactive or passive layer of an integrated circuit, etc.).

A method of coating at least a portion of an object according to thepresent invention includes providing an object in a defined volume(e.g., the object includes at least one surface). One or more nozzlestructures are provided. Each nozzle structure includes at least aninner opening and an outer opening concentric with the inner opening(e.g., the inner opening and the outer opening terminate at thedispensing end of each nozzle structure). The method further includesselecting a type of coating to be applied to the at least one surface ofthe object (e.g., one of an open matrix coating, a closed film coating,and an intermediate matrix coating). A first flow of a liquid spraycomposition is provided to the inner opening (e.g., the first flow ofliquid spray composition includes at least one of a biologically activeingredient, a polymer, and a solvent). A second flow of a liquid diluentcomposition is provided to the outer opening (e.g., the second flow ofthe liquid diluent composition includes at least one solvent, such as ahigh dielectric solvent when applying an open matrix coating). Aplurality of charged coating particles are generated forward of thedispensing end of each nozzle structure to apply a coating to the atleast one surface of the object. The plurality of charged coatingparticles are dispensed as a stream of a plurality of microdropletshaving an electrical charge associated therewith from the dispensing endof each nozzle structure by creating a cone-jet from the first andsecond flow at the dispensing end of each nozzle using a nonuniformelectrical field between the dispensing end of each nozzle structure andthe object. The plurality of charged coating particles (e.g., having anominal diameter of less than 10 micrometers) are formed as themicrodroplets evaporate. The method further includes moving theplurality of charged coating particles towards the at least one surfaceof the object to apply the coating thereon using the nonuniformelectrical field created between the dispensing end of each nozzlestructure and the object. Further, a flow rate of the second flow of theliquid diluent composition is controlled relative to a flow rate of thefirst flow of the liquid spray composition such that the plurality ofcharged coating particles forms the selected type of coating on the atleast one surface of the object (e.g., a uniform open matrix coating, auniform closed film coating, etc.).

Another method of coating at least a portion of an object includesproviding an object in a defined volume (e.g., the object including atleast one surface) and providing one or more nozzle structures. Eachnozzle structure includes at least an inner opening and an outer openingconcentric with the inner opening (e.g., the inner opening and the outeropening terminate at the dispensing end of each nozzle structure). Afirst flow of a liquid spray composition is provided to the inneropening (e.g., the first flow of liquid spray composition includes atleast a polymer and a solvent, such as a low dielectric constantsolvent, suitable to at least partially dissolve the polymer, and mayalso include biologically active material). A second flow of a liquiddiluent composition is provided to the outer opening (e.g., the secondflow of the liquid diluent composition includes at least one solventsuch as a high dielectric constant solvent). At least in one embodiment,the liquid diluent composition has a conductivity greater than 1 μScm⁻¹. A plurality of charged coating particles are generated forward ofthe dispensing end of each nozzle structure to apply a coating to the atleast one surface of the object. Generating the plurality of chargedcoating particles includes dispensing a stream of a plurality ofmicrodroplets having an electrical charge associated therewith from thedispensing end of each nozzle structure by creating a cone-jet from thefirst and second flow at the dispensing end of each nozzle using anonuniform electrical field between the dispensing end of each nozzlestructure and the object. The plurality of charged coating particles aremoved towards the at least one surface of the object to apply an openmatrix coating thereon using the nonuniform electrical field createdbetween the dispensing end of each nozzle structure and the object.

Yet another method of coating at least a portion of an object includesproviding an object in a defined volume (e.g., the object includes atleast one surface) and providing one or more nozzle structures (e.g.,each nozzle structure includes one or more openings terminating at adispensing end of each nozzle structure). One or more flows of liquidcompositions are provided to the openings and a plurality of chargedcoating particles are generated forward of the dispensing end of eachnozzle structure to apply a coating to the at least one surface of theobject. Generating the plurality of charged coating particles includesdispensing a stream of a plurality of microdroplets having an electricalcharge associated therewith from the dispensing end of each nozzlestructure by creating a cone-jet from the one or more flows at thedispensing end of each nozzle using a nonuniform electrical fieldbetween the dispensing end of each nozzle structure and the object. Theplurality of charged coating particles having a nominal diameter of lessthan 10 micrometers are formed as the microdroplets evaporate. Using thenonuniform electrical field between the dispensing end of each nozzlestructure and the object to generate the plurality of charged coatingparticles includes applying an electrical potential difference betweenthe dispensing end of each nozzle structure and the object being coatedso as to create the cone jet from the one or more flows at thedispensing end of each nozzle structure. The method further includesadjusting the electrical potential difference between the dispensing endof each nozzle structure and the object being coated as the thickness ofthe coating increases so as to maintain a stable cone jet at thedispensing end of each nozzle structure. Systems for carrying out thismethod are also provided.

Still another method of coating at least a portion of an object includesproviding an object in a defined volume (e.g., the object includes atleast one surface) and providing one or more nozzle structures. Eachnozzle structure includes one or more openings terminating at adispensing end of each nozzle structure. One or more flows of liquidcompositions are provided to the openings and a plurality of chargedcoating particles are generated forward of the dispensing end of eachnozzle structure to apply a coating to the at least one surface of theobject. Generating the plurality of charged coating particles includesdispensing a stream of a plurality of microdroplets having an electricalcharge associated therewith from the dispensing end of each nozzlestructure by creating a cone-jet from the one or more flows at thedispensing end of each nozzle using a nonuniform electrical fieldbetween the dispensing end of each nozzle structure and the object. Theplurality of charged coating particles having a nominal diameter of lessthan 10 micrometers are formed as the microdroplets evaporate. Themethod further includes detecting at least one characteristic associatedwith the cone-jet, determining the stability of the cone jet based onthe at least one characteristic, and adjusting one or more processparameters to maintain a stable cone-jet.

In one or more embodiments of the method, detecting at least onecharacteristic associated with the cone-jet includes imaging thecone-jet to determine at least one angle associated therewith, detectone or more flutters in the cone-jet, and/or detect bubbles in the oneor more flows. Systems for carrying out this method are also provided.

In yet another method of coating at least a portion of an object, themethod includes providing an object in a defined volume and providingone or more nozzle structures. Each nozzle structure includes a firstinner opening, a second intermediate opening concentric with the inneropening, and a third outer opening concentric with the first inneropening and second intermediate opening. The first inner opening, thesecond intermediate opening, and the third outer opening terminate atthe dispensing end of the nozzle structure. The method further includesproviding a first flow of a liquid spray composition to the first inneropening (e.g., the first flow of liquid spray composition includes atleast one biologically active ingredient), providing a second flow of aliquid spray composition to the second intermediate opening (e.g., thesecond flow of liquid spray composition includes at least one polymerand a solvent suitable for at least partially dissolving the polymer),and providing a third flow of a liquid diluent composition to the thirdouter opening (e.g., the third flow of the liquid diluent compositionincludes at least one solvent). A plurality of charged coating particlesare generated forward of the dispensing end of each nozzle structure toapply a coating to the at least one surface of the object. Generatingthe plurality of charged coating particles includes dispensing a streamof a plurality of microdroplets having an electrical charge associatedtherewith from the dispensing end of each nozzle structure by creating acone jet from the first, second, and third flows at the dispensing endof each nozzle structure using a nonuniform electrical field between thedispensing end of each nozzle structure and the object. The plurality ofcharged coating particles having a nominal diameter of less than 10micrometers are formed as the microdroplets evaporate. The plurality ofcharged coating particles include biologically active material at leastpartially encapsulated by the polymer.

Further, a coating sprayed by electrospray from a cone-jet provided withone or more flows of liquid compositions that include at least twoactive ingredients (e.g., the at least two active ingredients in the oneor more flows exist in a predetermined ratio) is described. The coatingincludes a plurality of particles adherent to one another but discrete.The plurality of particles have a nominal diameter of less than 500nanometers and each particle includes the at least two activeingredients in substantially the same predetermined ratio as the atleast two active ingredients exist in the one or more flows.

In one or more embodiments of the coating, the plurality of particleshave a nominal diameter of less than 200 nanometers; the at least twoactive ingredients include a polymer and biologically active material;the at least two active ingredients are uniformly distributed throughthe thickness of the coating; and open regions are present throughoutthe thickness of the coating.

The above summary of the present invention is not intended to describeeach embodiment or every implementation of the present invention.Advantages, together with a more complete understanding of theinvention, will become apparent and appreciated by referring to thefollowing detailed description and claims taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a general diagram illustrative of one embodiment of an objectcoating system, e.g., a nanoparticle generator system using electrospraytechniques for coating surfaces that includes a dual opening nozzle inaccordance with the present invention.

FIGS. 2A-2C are images of a capillary electrospray dispensing end (e.g.,spray head) progressing from the start of spray (FIG. 2A) to the“pulsating” mode (FIG. 2B) to the “cone-jet” mode (FIG. 2C) according tothe present invention.

FIG. 2D is a graph showing a current versus voltage curve forelectrospray of a particular solution.

FIGS. 3A-3C illustratively show three types of coatings that may beselected and/or applied according to the present invention including anopen matrix coating in FIG. 3A, a closed film coating in FIG. 3B, and anintermediate matrix coating in FIG. 3C.

FIG. 4 shows a general diagrammatical illustration of one embodiment ofan electrospray dispensing device including a ring electrode forcontrolling particle spread as well as for illustrating control ofnozzle to target surface distance for applying one or more of the typesof coatings such as generally shown in FIGS. 3A-3C.

FIG. 5 shows a general diagrammatical illustration of one embodiment ofan electrospray dispensing device including a ring electrode forcontrolling particle spread as well as a gas flow for use in controllingthe application of one or more of the types of coatings such asgenerally shown in FIGS. 3A-3C.

FIG. 6 shows a general diagrammatical illustration of one embodiment ofan electrospray dispensing device that includes a triple opening nozzlein accordance with the present invention, and further includes a ringelectrode for controlling particle spread as well as a gas flow for usein controlling the application of one or more of the types of coatingssuch as generally shown in FIGS. 3A-3C.

FIG. 7A shows a more detail diagram of one embodiment of a dual openingelectrospray dispensing apparatus according to the present inventionthat may be controlled for applying one or more of the types of coatingssuch as generally shown in FIGS. 3A-3C.

FIG. 7B shows a more detail diagram of one embodiment of a tripleopening electrospray dispensing apparatus according to the presentinvention that may be controlled for applying one or more of the typesof coatings such as generally shown in FIGS. 3A-3C.

FIG. 8 shows a general diagrammatical illustration of a configuration ofproviding multiple electrospray nozzle structures according to thepresent invention that may be employed in the coating system showngenerally in FIG. 1.

FIG. 9 shows a table of experimental conditions and outcome measures toassess impact of process parameters on achieving desired coatingsaccording to one or more examples provided herein.

FIGS. 10 a-h show design of experiment image results for the parametersets outlined in FIG. 9 according to one or more examples providedherein.

FIG. 11 shows a table of the relationship of process parameters toexperimental outcome variables according to one or more examplesprovided herein.

FIG. 12 shows a graph of hysterisis effect on the relationship betweenvoltage and current through the spray target while operating theelectrospray technique according to one or more examples providedherein.

FIG. 13 shows a table of stent and coating weights for each lot ofvarious coating polymers and surfaces according to one or more examplesprovided herein.

FIGS. 14-16 show graphs of coating net weights for lots of stentsprovided with open matrix coatings and closed film coatings according toone or more examples provided herein.

FIG. 17 shows a table regarding coating transfer efficiency as afunction of coating polymer, surface, and solvents, according to one ormore examples provided herein.

FIG. 18 shows a graph of a profilometer scan showing coating thicknessaccording to one or more examples provided herein.

FIGS. 19 a-c show cross-sectional images of three coatings producedaccording to one or more examples provided herein.

FIGS. 20 a-f show SEM images of coatings according to one or moreexamples provided herein.

FIG. 21 shows a table for use in describing the images of FIGS. 20 a-faccording to one or more examples provided herein.

FIG. 22 shows an FTIR Spectra of a couple of coatings according to oneor more examples provided herein.

FIGS. 23 a-b show images of the effect of humidity on open matrixcoatings and closed film coatings according to one or more examplesprovided herein.

FIG. 24A shows a table of solutions and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 24B shows respective images (highermagnification and lesser magnification) of the resulting coatingscorresponding to the Sample #'s shown in the table.

FIG. 25A shows a table of solutions and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 25B shows respective images (highermagnification and lesser magnification) of the resulting coatingscorresponding to the Sample #'s shown in the table.

FIG. 26A shows a table of a solution and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 26B shows respective images (highermagnification and lesser magnification) of the resulting coatingcorresponding to the Sample # shown in the table.

FIG. 27A shows a table of solutions and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 27B shows respective images (highermagnification and lesser magnification) of the resulting coatingscorresponding to the Sample #'s shown in the table.

FIG. 28A shows a table of solutions and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 28B shows respective images (highermagnification and lesser magnification) of the resulting coatingscorresponding to the Sample #'s shown in the table.

FIG. 29A shows a table of solutions and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 29B shows respective images (highermagnification and lesser magnification) of the resulting coatingscorresponding to the Sample #'s shown in the table.

FIG. 30A shows a table of a solution and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein, and FIG. 30B shows respective images (highermagnification and lesser magnification) of the resulting coatingcorresponding to the Sample # shown in the table.

FIG. 31 shows a table of a solution and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein.

FIG. 32 shows respective images (higher magnification and lessermagnification) of the resulting coating corresponding to the Sample #shown in the table of FIG. 31.

FIG. 33 shows a table of a solution and parameters used in theapplication of one or more coatings according to one or more examplesprovided herein.

FIG. 34 shows respective images (higher magnification and lessermagnification) of the resulting coating corresponding to the Sample #shown in the table of FIG. 33.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present invention shall generally be described with reference toFIGS. 1-8. Various examples shall then be described with reference toFIGS. 9-34. It will become apparent to one skilled in the art thatelements from one embodiment may be used in combination with elements ofother embodiments, and that the present invention is not limited to thespecific embodiments described herein but only as described in theaccompanying claims. For example, one or more parameters may be used forproviding control of one or more coating methods described herein.

The present invention provides for coated objects (e.g., coated stentstructures) and also systems and methods for coating objects (e.g.,coating of medical devices, depositing a film on any object such as fortexturing the surface thereof, providing a protective layer on anobject, providing a textured surface to improve cellular adherenceand/or biocompatibility, constructing an active or passive layer of anintegrated circuit, etc.). With use of the present invention, forexample, selected types of coatings having uniform properties can beaccomplished. Further, the present invention provides for the efficientand cost effective use of coating materials.

An electrospray coating system, such as electrospray coating system 10illustratively shown in FIG. 1, can be controlled so as to provide forone or more selected types of coatings according to the presentinvention. For example, the electrospray coating system 10 may becontrolled to provide an open matrix coating on one or more surfaceportions of an object, a closed film coating on one or more surfaceportions of an object, or an intermediate matrix coating on one or moresurface portions of an object.

FIGS. 3A-3C illustratively show three types of coatings that may beselected and/or applied according to the present invention including anopen matrix coating in FIG. 3A, a closed film coating in FIG. 3B, and anintermediate matrix coating in FIG. 3C. Such coatings can be selectedfor application on one or more surface portions of an object 600. Suchselection may be performed manually or automatically. Generally, theselection of the type of coating to be applied may include a userdetermining that it is desirable to use one or more of the types ofcoatings to obtain one or more types of functionality provided by thecoating. Selection may involve a user operating a system and settingvarious parameters or selecting various compositions to be used in thespraying process so as to apply a particular selected coating, or mayinclude user selection of a coating type on a system such that thesystem automatically selects one or more parameters or variouscompositions to be used in the spraying process so as to apply aparticular selected coating, or a combination of both.

Generally as described herein, the selected coating type may be appliedusing two or more different types of liquid compositions (e.g., a liquidspray composition and a liquid diluent composition provided at two ormore concentric openings at a dispensing end of a nozzle structure)and/or under one or more conditions or controlled parameters accordingto the present invention. For example, as described herein, an openmatrix coating may be applied to a surface of an object by controllingthe type of liquid diluent composition and/or the conductivity of acomposition provided at an outer opening of a dual opening nozzlestructure, or by controlling the ratio of a liquid diluent compositionprovided at an outer opening of a dual opening nozzle structure to theliquid spray composition provided at an inner opening of a dual openingnozzle structure.

As used herein, an open matrix coating refers to a coating wherein asupermajority (i.e., greater than two-thirds) of the particles used tocreate the coating are visibly discrete but attached creating arelatively irregular coating compared to a closed film coating. In otherwords, when an open matrix coating is viewed using microscopy, theparticles used to form the coating can be visually separated by theviewer into discrete particles even though such particles are attached,or otherwise coupled, to one or more other particles of the coating.

An open matrix coating 702 is illustratively shown in FIG. 3A applied tosurface 708. The open matrix coating 702 includes discrete particles 704attached, or otherwise coupled, to one or more other particles 704 ofthe coating 702.

The open matrix coating has visibly distinct open regions 707 appearingdarker than the surface 706 of the coating 702 when viewed usingscanning electron microscopy (SEM). Such opening regions 707 extend atleast one or more nominal diameters of the particles 704 deeper into thesurface 706 (e.g., from the upper most surface of the outer mostparticles at the surface 706 of the coating 702). At least in oneembodiment, such opening regions 707 exist throughout the thickness ofthe coating 702 as shown in FIG. 3A. Further, particles with distinctboundaries and shape similar to those seen on the surface 706 of thecoating are visible using SEM in one or more planes beneath the surface706 of the coating.

At least in one embodiment of the open matrix coating, the particles aresubstantially round particles. As used herein, substantially roundparticles refers to particles that are not elongated fiber particles;elongated fiber particles as used herein are fiber particles that have abody length that is at least ten (10) times the diameter of a maximumcross-section taken at any point along the length of the particle. Inother words, a substantially round particle does not have an elongatedbody but is more spherically shaped, although such particles will notnecessarily be spherical.

Generally, the surface area at the upper surface 706 of the coating 702is a rough surface that can be characterized in one or more differentmanners. One manner of characterizing a rough surface of the open matrixcoating is based on the cross-section particle size of the particles ofthe coating being deposited. At least in one embodiment, the nominalcross-section particle size is represented by the nominal diameterthrough the center of the particles. In one embodiment, the nominaldiameter for particles of a rough open matrix coating according to thepresent invention is in the range of about 1 nm to about 2000 nm. Inanother embodiment, the cross-section nominal diameter through thecenter of the particles is greater than about 10 nm, in anotherembodiment less than about 1000 nm, in another embodiment less thanabout 500 nanometers, and in another embodiment less than about 200 nm.

Alternatively, or in addition to other manners of characterizing therough surface of the coating 702, a rough surface may be characterizedbased on a comparison of the surface area of the rough surface relativeto the surface area of a completely smooth surface (i.e., a surface withno structure, e.g., valleys, peaks, etc.) having a substantiallyidentical shape as the rough surface, e.g., the shape of the structureupon which a rough portion is formed. In one embodiment of the presentinvention, a rough surface is a generally homogenous surface (i.e., asurface structure without any substantial irregularities from one partof the surface to another part of the surface such as, for example, deepdepressions, large spikes, unusually large particles compared to theother particles of the layer, etc.) that has a surface area greater thanabout 1.2 times the surface area of a completely smooth surface having asubstantially identical shape (i.e., substantially identical shapeshaving the same base dimensional characteristics, e.g., in the case of aplanar surface the occupancy area of both the completely smooth andrough surface are equivalent). However, the surface shape may be of aplanar shape, a curved shape, or any other shape. In yet anotherembodiment, the roughness of the surface has a surface area that isgreater than about 1.5 times the surface area of a completely smoothsurface having a substantially identical shape.

For example, as shown in FIG. 3A, the rough surface 706 of coating 702has a generally planar shape. The surface area of the rough surface 706can be compared to a surface area (XY) (only the x axis is shown withthe y axis extending into the page) of a completely smooth surface 708having a planar shape, i.e., a shape identical to the shape of the roughsurface 706. Therefore, at least in one embodiment, the surface area ofrough surface 706 of the coating 702 is greater than about 1.2(XY). Yetfurther, in another embodiment, the surface area of rough surface 706 ofthe coating 702 is greater than about 2.0(XY).

As used herein, a closed film coating refers to a coating wherein asupermajority (i.e., greater than two-thirds) of the particles used tocreate the coating are not visibly discrete, but rather have flowedtogether to form a relatively smooth coating as compared to an openmatrix coating. In other words, when a closed film coating is viewedusing microscopy, the particles used to form the coating are notvisually separable into discrete particles by the viewer but rather thecoating is seen as a generally smooth coating with no or littleirregularity.

A closed film coating 712 is illustratively shown in FIG. 3B. The closedfilm coating 712 includes substantially no discrete particles, butrather the coating 712 has an upper surface 716 that is smooth andflowing. In other words, the surface area of the smooth surface 716 issubstantially equal to a surface area (XY) (only the x axis is shownwith the y axis extending into the page) of a completely smooth surface718 having an identical shape, or at least is less than about 1.1(XY).

As used herein, an intermediate matrix coating refers to a coatingwherein less than a supermajority (i.e., less than two-thirds) of theparticles used to create the coating are visibly discrete, however, morethan superminority (i.e., more than one third) of the particles arevisibly discrete (e.g., in such a coating, many particles are visiblydiscrete with flowing material generally existing therebetween). Inother words, when an intermediate matrix coating is viewed usingmicroscopy, between one third to two thirds of the particles used toform the coating are visually separable into discrete particles by theviewer, with the remainder of the coating being a flowing materialconnecting such particles forming a coating that is slightly irregularcompared to a closed film coating but less irregular than an open matrixcoating.

An intermediate matrix coating 722 is illustratively shown in FIG. 3C.The intermediate matrix coating 722 includes some visibly discreteparticles 724, and has an upper surface 726 that is slightly rough. Inother words, the surface area of the slightly rough surface 726 is lessrough than an open matrix coating but rougher than a closed filmcoating.

As used herein, when reference is made to a uniform coating, theuniformity extends through the entire thickness of a selected coatingunless otherwise stated. For example, the structure of a uniform openmatrix coating (i.e., wherein the particles are visibly discrete butconnected to one or more other particles) is substantially the samethroughout the entire thickness of the coating (e.g., the particles arevisibly discrete at the surface of an object being coated as well asthroughout the coating including the upper rough surface of the openmatrix coating).

One will recognize that two or more selected types of coatings may beapplied to create a combined coating of two or more selected coatings(e.g., a closed film coating overlaid with an open matrix coating). Insuch a case, uniformity of such selected layers would apply to therespective layers.

At least in one embodiment, an open matrix coating may be sprayed byelectrospray from a cone jet provided with one or more flows of liquidcompositions (e.g., such as using a dual opening nozzle structure suchas described herein, a single opening nozzle structure, etc). The one ormore flows include at least two active ingredients. The at least twoactive ingredients in the one or more flows exist in a predeterminedratio. The coating includes a plurality of particles adherent to oneanother but discrete such as described above with reference to an openmatrix coating. The plurality of particles have a nominal diameter ofless than 500 nanometers, and may even have a nominal diameter of lessthan 200 nanometers. Each particle of the coating includes the at leasttwo active ingredients in substantially the same predetermined ratio asthe at least two active ingredients exist in the one or more flows. Asused in this context, the term substantially refers to a deviation of+/−20%.

In one or more further embodiments of such a coating, the at least twoactive ingredients include a polymer and biologically active material(e.g., the biologically active ingredient may be encapsulated by thepolymer or they may exist in more of a matrix form. Further, the atleast two active ingredients are uniformly distributed through thethickness of the coating and open regions like those described withreference to the open matrix coating are present throughout thethickness of the coating.

One embodiment of an electrospray coating system 10 according to thepresent invention is shown in FIG. 1. The electrospray coating system 10employs the generation of particles, such as, for example,nanoparticles, for use in coating objects, such as medical devices(e.g., coating such devices with polymers and/or drugs, with oneselected coating or more than one selected coating).

As further described herein, the systems and methods according to thepresent invention may use one or more electrospray apparatus having dualopening nozzle structures, or one or more nozzle structures that havemore than two openings at the dispensing ends thereof, such as thatpreviously described in U.S. Pat. No. 6,093,557 to Pui, et al., entitled“Electrospraying Apparatus and Method for Introducing Material intoCells,” issued 25 Jul. 2000 (e.g., dual capillary configurations), andalso described in the papers entitled, “Electrospraying of ConductingLiquids for Dispersed Aerosol Generation in the 4 nm to 1.8 μm DiameterRange” by Chen, et al., J. Aerosol Sci., Vol. 26, No. 6, pp. 963-977(1995), and entitled “Experimental Investigation of Scaling Laws forElectrospraying: Dielectric Constant Effect” by Chen, et al., AerosolScience and Technology, 27:367-380 (1997), or may use a single ormultiple nozzle structure electrospray apparatus such as described inU.S. Patent Application US-2002-0007869-A1, entitled “High MassThroughput Particle Generation Using Multiple Nozzle Spraying,”published on 24 Jan. 2002, or may use one or more nozzle structuresdescribed in US 2003/0143315 A1, entitled “Coating Medical Devices,”published 31 Jul. 2003, which are all hereby incorporated in theirentirety by reference thereto.

As shown in FIG. 1, the illustrative electrospray coating system 10employs a dispensing apparatus 19 to establish a spray of coatingparticles 28 (e.g., spray of microdroplets which evaporate to form aspray of coating particles). The dispensing apparatus 19 includes atleast one nozzle structure 18 that includes at least two concentricopenings 27, 29 (e.g., concentric about axis 39) that terminate at thedispensing end 23 thereof. Openings that terminate at the dispensing end23 do not need to terminate in a single plane (e.g., a plane orthogonalto axis 39 along which the nozzle structure 18 extends. Rather, thetermination of one of the openings may be closer to the object 15 beingcoated than the other (e.g., the inner opening may terminate closer tothe object 15). The openings receive source material to establish thespray of coating particles 28 forward of the dispensing end 23, e.g., inthe direction of the object 15 to be coated. The coating particles 28are moved toward at least one surface 13 of the object 15 (e.g., medicaldevice) to form a coating 105 thereon.

The object 15 is located in a defined volume (shown generally by thedashed line 17) where the coating particles 28 are provided. The definedvolume 17 may, for example, be a reactor chamber, a chamber of a coatingsystem, a vacuum chamber, a pressurized and/or heated chamber, a volumeof open air space, a chamber including a particular gas environment,etc.

The system 10 includes a source holding apparatus 30 for providing afirst liquid spray composition to an inner opening 27 of the twoconcentric openings terminating at the dispensing end 23 of the nozzlestructure 18 such as under control of control mechanism 55, e.g.,hardware and/or software control, via feeder/flow control 24. The system10 further includes a source holding apparatus 32 for providing a secondliquid diluent composition to an outer opening 29 of the two concentricopenings terminating at the dispensing end 23 of the nozzle structure 18under control of control mechanism 55, e.g., hardware and/or softwarecontrol, via feeder/flow control 25. An electrospray nozzle structure 18can deliver a controlled feed rate of source material in theestablishment of a spray of coating particles within the envelope of thenozzle structure. The nozzle structure 18 is configured to operate in acone-jet mode as further described herein to provide a spray of coatingparticles 28 to the defined volume 17 where the object 15 is locatedusing the source material (e.g., the first flow of liquid spraycomposition and the second flow of liquid diluent composition).

With further reference to FIG. 1, the nozzle structure 18 of thedispensing device 19 may include a nozzle structure having any one ofvarious configurations and employing any number of different components,e.g., dual capillary electrodes, micro-machined tapered openings aloneor in combination with capillary electrodes, etc. For example, aspreviously indicated, the nozzle structure may include one or morenozzle structures as described in U.S. Pat. No. 6,093,557 or U.S. PatentApplication US-2002-0007869-A1. Various types of nozzle structures, anddispensing devices with which they may be used, are shown and describedherein. However, nozzle structures described in documents incorporatedherein may provide further nozzle structures that may be used accordingto the present invention and/or may provide additional descriptionregarding the nozzle structures that have also been described generallyherein.

The nozzle structure 18 of the electrospray dispensing device 19provides a charged spray with a high concentration of charged particles.Generally, the concentration of charged particles in the spray is in therange of about 10⁵ particles per cubic centimeter (particles/cc) toabout 10¹² particles/cc. Due to the space charge effect, i.e., theeffect created by the charge repulsion of charged particles, a spray ofsubstantially dispersed particles having the same polarity charge isprovided with the particles distributed substantially uniformly across aspray area.

As used herein, the term substantially dispersed particles refers touniformly and/or nonuniformly sized particles separated by an appliedrepulsive electrostatic force. Thus, the electrospray process is aconsistent and reproducible transfer process. Further, because thecharged particles of the spray repel one another, agglomeration of theparticles is avoided. This results in a more uniform particle size.“Substantially dispersed” particles are not to be confused withmonodisperse particles which involves the general degree of uniformityof the particles sprayed, e.g., the standard deviation of the particlesfrom a nominal size.

Generally, according to the configuration as shown at FIG. 1, the chargeis applied by concentration of charge on the spray of coating particlesthrough evaporation (at least partially) in an established electricalfield 43 prior to the coating particles forming a selected coating 105on the object 15. In other words, as further described herein the liquidsprayed generally evaporates to concentrate a charge of a liquid portionthereof on the coating particles, e.g., on the active ingredient of theparticles. This results in the spray of charged coating particles 28 asdescribed further herein.

FIG. 1 generally shows a diagrammatical illustration of the operation ofthe electrospray coating system 10 for establishing a charged spray 28from the nozzle structure 18. The nozzle structure 18 receives a firstflow of the liquid spray composition from the material source holdingapparatus 30 and a second flow of the liquid diluent composition fromthe material source holding apparatus 32. For example, the materialsource holding apparatus 30 may include a liquid spray compositionincluding drug active ingredients and a polymer at least partiallydissolved in a solvent suitable to dissolve such a polymer therein.Further, for example, the material source holding apparatus 32 mayinclude a liquid diluent composition including the same or a differentsolvent as the solvent in the liquid spray composition.

Generally, a conductive material 47, e.g., a conductive plate, positionsthe nozzle structure 18 in a particular configuration. For example, theconductive material 47 may be adapted to be connected to a high voltagesource 20. The nozzle structure 18 includes a conductive structure,e.g., a capillary tube structure such as illustratively shown in FIGS.7A and 7B, which defines orifices, e.g., openings 27 and 29, thatterminate at the dispensing end 23 of the nozzle structure 18 forproviding the flows of the liquid compositions.

Although various configurations for the source material holdingapparatus 30 and 32 may be used according to the present invention, inone embodiment a single holding apparatus for each liquid composition isused to feed the respective liquid composition to the nozzle structure18. One will recognize that any number of different and separate holdingapparatus may be used or hold various different compositions and providedifferent compositions to one or more different nozzle structures (e.g.,such as when multiple nozzle structures are used).

In one or more embodiments, the liquid spray composition and or liquiddiluent composition may be pushed or pulled through the openings at thedispensing end 23 of the nozzle structure 18, e.g., pushed by a pump. Inone embodiment, a compressed gas source, e.g., an inert source that isnon-reactive with the composition, is provided to compress thecomposition and force fluid to flow through openings 27 and 29 of thenozzle structure 18. Although, in one embodiment, a compressed gassource may be used to provide such composition flow, other methods ofproviding such flow may also be used. For example, syringe pumps foreach liquid composition may be used to establish the flow of material orthe flow may also be controlled with use of a liquid pump (e.g., asyringe pump, a gravity feed pump, a pressure regulated liquidreservoir, etc.), a mass flow controller, or any other flow controldevices suitable for feeding source material to the nozzle structure 18as would be known to one skilled in the art.

The nozzle structure 18 positioned by and electrically coupled to theconductive structure 47 functions as a first electrode of theelectrospray dispensing apparatus 19 with the dispensing end 23 of thenozzle structure 18 being positioned for dispensing chargedmicrodroplets toward the object 15, or a surface 13 thereof. In theexemplary embodiment of FIG. 1, to set up the electric field 43, theobject 15 may function as a second electrode structure, e.g., a groundedobject 15 as shown by ground 81. An electrical potential difference isapplied between the first electrode conductive structure 47 and thesecond electrode or grounded object 15 that is electrically isolatedfrom the first electrode. One skilled in the art will recognize that theelectrodes may be formed using one or more conductive elements, and suchelectrodes may take one of various different configurations. Further,the second electrode may also have a suitable opposite charge appliedthereto (i.e., opposite to the first electrode).

Generally, in operation, a first flow of the liquid spray compositionfrom the material source holding apparatus 30 and a second flow of theliquid diluent composition from the material source holding apparatus 32is provided through the openings 27 and 29 of the nozzle structure 18,respectively. At least in one embodiment, a meniscus is foamed at thedispensing end 23 where the inner opening 27 has an inner diameter inthe range of about 6 microns to about 2 millimeters and an outerdiameter in the range of about 8 microns to about 2.5 millimeters, andthe outer opening 29 has an inner diameter in the range of about 15microns to about 5 millimeters and an outer diameter in the range ofabout 30 microns to about 7 millimeters. Such dimensions are based onestimated clearances for different sizes of stainless steel capillariesand their wall thicknesses.

An electrical potential difference is applied to establish thenonuniform field 43 between the first electrode at the dispensing end 23of the nozzle structure 18 and the second electrode (e.g., the groundedobject 15). For example, a high positive voltage may be applied to thefirst electrode conductive structure 47 with the second electrode object15 being grounded (e.g., the second electrode may also have a suitableopposite charge applied thereto; opposite to the first electrode. Forexample, a voltage difference that provides an electric field intensitygreater than 4 kV/cm is used in order to provide cone-jet operation ofthe dispensing apparatus 19.

As used herein, nonuniform electric field refers to an electric fieldcreated by an electrical potential difference between two electrodes.The nonuniform electric field includes at least some electric fieldlines that are more locally concentrated at one electrode relative tothe other electrode, e.g., more concentrated at the dispensing end 23relative to the second electrode or a grounded object 15. In otherwords, for example, at least some of the field lines are off axisrelative to the longitudinal axis 39 that extends through the center ofthe openings 27 and 29. For example, the grounded object 15 ispositioned forward of dispensing end 23 and is of a size and/or includesat least a portion that is located at a position away from thelongitudinal axis 39.

In various embodiments, the second electrode may also, or in thealternative, include one or more loop electrodes, plate electrodes,grounded surfaces, etc. The object 15 may still be coated even if adifferent electrode structure is used to produce the charged particles.

For example, a loop electrode 40 as shown in FIG. 1 may be positionedforward of the dispensing end 23 to create the electric field forproviding highly charged particles in the defined volume 17 in which theobject 15 is positioned. With the particles provided in the definedvolume, the highly charged particles are moved toward a grounded object15 as the loop electrode 40, at least in one embodiment is position inproximity to the surface of the object 15 to be coated. As such, it willbe recognized that coating the object 15 using the electrospray coatingsystem 10 shown generally in FIG. 1 may involve providing particles in adefined volume in which the object is provided, and thereafter, movingthe particles toward the object forming a coating thereon. In addition,alternatively, the particles may be formed and moved toward the objectfor coating thereon simultaneously with their formation. For example,the object 15 may be grounded to set up the nonuniform electric fieldfor producing the charged particles in the defined volume in which theobject 15 is provided with the same field also providing for themovement of such charged particles towards the object 15 so as to form acoating thereon.

In one exemplary embodiment, where the liquid spray composition includesan active ingredient, the liquid spray composition is flowed through theinner opening 27 of the nozzle structure 18 and the liquid diluentcomposition is flowed through the outer opening 29 of the nozzlestructure 18. Generally, the resulting blended flow of the liquidcompositions at the dispensing end 23 has an electrical conductivityassociated therewith. In other words, as the liquid compositionsprogress through the openings, the potential difference between thefirst and second electrodes, which creates the electric field therebetween, strips the liquid of one polarity of charge, i.e., the negativecharge is stripped when a high positive voltage is applied to the firstelectrode, leaving a positively charged microdroplet to be dispensedfrom the dispensing end 23. For example, the meniscus at the dispensingend 23 may form a cone-jet for dispensing a spray of microdropletsincluding the active ingredients when forces of a nonuniform fieldbalance the surface tension of the meniscus. The spray of microdropletsfurther becomes more positive in the nonuniform electric field.

As the microdroplets evaporate, the charge of the microdropletsconcentrates on the active ingredients resulting in a spray of chargedcoating particles. The amount of charge on the microdroplet, and thusthe amount of charge on a particle after evaporation, is based at leastupon the conductivity of the fluid composition used to spray themicrodroplet, the surface tension of the fluid composition, thedielectric constant of the fluid composition, and the feed flow ratethereof. At least in one embodiment, the electric charge concentrated ona particular particle is greater than about 30% of a maximum charge thatcan be held by the microdroplets, without the microdroplet beingshattered or torn apart, i.e., greater than about 30% of the Rayleighcharge limit. At least in one another embodiment, the charge is greaterthan 50% of the Rayleigh charge limit. At 100%, the surface tension ofthe microdroplet is overcome by the electric forces causing dropletdisintegration. The nonuniform electric field also provides forcontainment of particles and/or direction for the particles which wouldotherwise proceed in random directions due to the space charge effect.

One skilled in the art will recognize that the voltages applied may bereversed. For example, the first electrode may be grounded with a highpositive voltage applied to the second electrode. In such a case, theparticles would have a negative charge concentrated thereon. Further,any other applied voltage configuration providing a nonuniform electricfield to establish the charged spray of coating particles may be used.

The nonuniform electric field can be provided by various configurations.For example, the second electrode may be any conductive materialgrounded (or having a suitable opposite charge applied thereto (i.e.,opposite to the first electrode)) and positioned to establish theformation of a spray of coating particles 28 from the dispensing end 23of the nozzle structure 18, e.g., the second electrode may be a groundedring electrode, a grounded elongated element positioned in the interiorvolume of a stent structure, etc. The second electrode may also belocated at various positions, such as just forward of the nozzlestructure 18, or located farther away from the nozzle structure 18 andcloser to object 15.

The strength of the field may be adjusted by adjustment of the distancebetween the first and second electrodes. Different field strengths mayresult in relatively different areas D upon which particle spray isprovided, at least in part due to the space charge effect of the sprayof particles 28. One skilled in the art will recognize that one or morecomponents of the dispensing apparatus 19 may be moved relative to theothers, e.g., the object 15 relative to the nozzle structure 18 or viceversa, to facilitate adjustment of field strength, and control one ormore parameters according to the present invention to form a selectedtype of coating.

Further, the object 15 and/or the dispensing apparatus 19 (or anycomponent thereof) may be moved in any one or more different directionsas represented generally by the horizontal/vertical movement arrows 101and radial movement arrow 102 prior to, during, or after the coatingprocess for any particular reason. Such movement of the object 15 or anyelements of the coating system 10 may be performed using any apparatusconfigured for the desired motion. The present invention is not limitedto any particular structure for providing such movement. Further, thepresent invention is not limited to movement of any elements of thecoating system 10 or the object 15 during the coating process. In otherwords, for example, the object 15, such as a medical device, may remainin a fixed position within the defined volume 17 as the coating processis performed.

The electrospray nozzle structure 18 used for particle generation asdescribed herein is operable in a cone-jet mode when an appropriatevoltage is applied for creation of the nonuniform electric field. Forexample, FIGS. 2A-2C are images of a capillary electrospray dispensingend (e.g., nozzle spray head) progressing from the start of spray (FIG.2A) to a “pulsating” mode (FIG. 2B) to a “cone-jet” mode (FIG. 2C)according to the present invention.

FIG. 2B shows a magnified view of the dispensing end (e.g., capillarytip) operating in pulsating mode and the meniscus of fluid is clearlyvisible. In FIG. 2C, the dispensing end is operating in the cone-jetmode where the electric field forces the composition being sprayed intoa sharp point from which a nanofibril can be seen emerging therefrom.This fibril is unstable and breaks up into charged particles accordingto the present invention (e.g., a solvent carrier and solute). Thesolvent evaporates due to the extremely high surface area. FIG. 2D showsa graph indicating the current versus voltage curve for electrospray ofa particular solution. Note that a particular voltage is needed for thenozzle to operate in cone-jet mode and that such a voltage may needadjustment to maintain a stable cone-jet mode. A stable cone-jet mode ofoperation is of importance when applying a uniform selected type ofcoating to an object such as described herein.

As used herein, a stable cone jet refers to a cone jet that does notflutter between a cone jet mode and a non-cone-jet mode (e.g., pulsatingmode). Further, such a stable cone-jet may exhibit a dark tip appearancewith no corona discharge being present.

As shown in FIG. 2C, a cone-jet 100 is formed at the dispensing end 23of the nozzle structure 18. The cone-jet 100 extends from the dispensingend 23 to a point or tip 109, that, at least in one embodiment, lies onaxis 39. An angle 104 is formed between the cone-jet 100 and a plane 106lying orthogonal to axis 39 at the tip 109. When the angle 104 decreasessuch that it looks more like the meniscus of FIG. 2B, the cone-jet ismore likely to move into a pulsating mode of operation. As such, bycontrolling the process to maintain a desired angle 104 of the cone-jet,a stable cone-jet can be achieved according to the present invention asfurther described herein.

As used herein, coating refers to forming a layer or structure on asurface. The coated layer or structure formed on the surface may be acoating that adheres to an underlying layer or the surface 13, or acoating that does not adhere to the surface or an underlying layer. Anylevel of adherence to the surface 13 or an underlying layer iscontemplated according to the present invention. For example, a coatingformed on surface 13 of the object 15 may be formed as a sheath, about astructure (e.g., a stent structure) without necessarily having adhesionbetween the layer and the structure.

Likewise, an adhesion layer may be deposited on an object 15 prior toforming a coating on the object 15 such that greater adhesion isaccomplished. The adhesion layer may also be coated on the surface 13 ofthe object 15 employing methods and/or systems according to the presentinvention.

Various embodiments of the coating methods and systems described aresuitable to allow one or more objects to be coated as a batch. However,the present invention is not limited to only coating objects such asmedical devices in batches, i.e., coating a group of one or more devicesin one batch process followed by coating a second group of one or moredevices in a second batch process. The methods and systems of thepresent invention can be utilized to continuously run objects throughthe systems such that the process does not have to be started andstopped for coating the objects in batches. In other words, a pluralityof objects such as medical devices can be coated through a continuousprocess.

In one or more of the embodiments of the present invention, single ormultiple coatings can be applied to objects, separately orsimultaneously. For example, a coating sprayed may include multiplematerials, different nozzle structures may be provided with differentsource materials for controlling and spraying different coatingmaterials, different nozzle structures may be controlled for use duringdifferent time periods so as to provide different layers of coatingmaterials on at least a portion of the object, multiple layers may besprayed using the same or different source materials (e.g., forming asomewhat laminated coating), the entire object or just a portion of theobject may be coated (e.g., a charge could be applied to a portion ofthe surface to attract all of or a majority of the sprayed particles tothe charged portion), different portions of the object may be sprayedwith a thicker coating than the remainder of the object, and/or maskingmaterials may be used to mask certain portions of the object from havingcoating applied thereto.

As indicated above, the present invention contemplates applying onelayer or multiple layers of the same or different types of coating(e.g., an open matrix coating, a closed film coating, and anintermediate matrix coating, in any combination). Such layers mayperform identical or different functions (e.g., to provide forbiocompatibility, to control drug release, etc.). Further, the one ormore layers may be applied to conductive or non-conductive surfaces.

The object 15 may be a medical device amenable to the coating processesdescribed herein. The medical device, or portion of the medical device,to be coated or surface modified may be made of metal, polymers,ceramics, composites or combinations thereof, and for example, may becoated with one or more of these materials. For example, glass, plasticor ceramic surfaces may be coated. Further, the present invention may beused to form a coating on surfaces of other objects as well, e.g., metalsubstrates or any other surfaces that may be rendered conductive (e.g.,whether flat, curved, or of any other shape).

Although the coatings described herein may be used to coat a vascularstent, other medical devices within the scope of the present inventioninclude any medical devices such as those, for example, which are used,at least in part, to penetrate and/or be positioned within the body of apatient, such as, but clearly not limited to, those devices that areimplanted within the body of a patient by surgical procedures. Examplesof such medical devices include implantable devices such as catheters,needle injection catheters, blood clot filters, vascular grafts, stentgrafts, biliary stents, colonic stents, bronchial/pulmonary stents,esophageal stents, ureteral stents, aneurysm filling coils and othercoiled devices, reconstructive implants, trans myocardialrevascularization (“TMR”) devices, percutaneous myocardialrevascularization (“PMR”) devices, lead wires, implantable spheres,pumps, dental implants, etc., as are known in the art, as well asdevices such as hypodermic needles, soft tissue clips, holding devices,and other types of medically useful needles and closures. Any exposedsurface of these medical devices may be coated with the methods andsystems of the present invention.

The source material held in the source holding apparatus 30 may be anysource of material (e.g., such as coating materials described hereinincluding solvents and active ingredients) which can be provided in thedefined volume in particle form as described according to the presentinvention. In one or more embodiments, the source material in sourceholding apparatus 30 is a liquid spray composition that may include asolution, a suspension, a microsuspension, an emulsion, a microemulsion,a gel, a hydrosol, or any other liquid compositions that when providedaccording to the present invention results in the generation ofparticles.

In one embodiment according to the present invention, the liquid spraycomposition may include at least one of a biologically activeingredient, a polymer, and a solvent (e.g., a solvent suitable to atleast partially dissolve the polymer). Further, for example, such liquidspray compositions may include a biologically active ingredient, apolymer, and a solvent suitable to at least partially dissolve thepolymer.

As used herein, an active ingredient refers to any component thatprovides a useful function when provided in particle form, particularlywhen provided as nanoparticles. The present invention is particularlybeneficial for spraying nanoparticles and also is particularlybeneficial for spraying particles including biologically activeingredients.

As such, the term “active ingredient” refers to material which iscompatible with and has an effect on the substrate or body with which itis used, such as, for example, drug active ingredients, chemicalelements for forming nanostructures, materials for modifying local celladherence to a device, materials for modifying tissue response to adevice surface, materials for modifying systemic response to a device,materials for improving biocompatibility, and elements for filmcoatings, e.g., polymers, excipients, etc.

The term “biologically active ingredient” or “biologically activematerial or component” is a subset of active ingredient and refers tomaterial which is compatible with and has an effect (which may, forexample, be biological, chemical, or biochemical) on the animal or plantwith which it is used and includes, for example, medicants such asmedicines, pharmaceutical medicines, and veterinary medicines, vaccines,genetic materials such as polynucleic acids, cellular components, andother therapeutic agents and drugs, such as those described herein.

As used herein, the term particle, and as such nanoparticle, includessolid, partially solid, and gel-like droplets and microcapsules whichincorporate solid, partially solid, gel-like or liquid matter. Particlesprovided and employed herein may have a nominal diameter as large as 10micrometers.

As used herein, nanoparticle refers to a particle having a nominaldiameter of less than 2000 nm. The present invention is particularlybeneficial in spraying nanoparticles having a nominal diameter greaterthan 1 nanometer (nm), particles having a nominal diameter less than1000 nm, particles having a nominal diameter of less than 500 nm,particles having a nominal diameter of less than 200 nm, and particleshaving a nominal diameter of less than 100 nm.

Further, the particles used for coating as described herein are, in atleast one embodiment, monodisperse coating particles. As used herein,monodisperse coating particles are coating particles that have ageometrical standard deviation of less than 1.2. In other words, thestandard deviation with respect to mean particle size of particlesprovided according to the present invention is, at least in oneembodiment, less than or equal to 20%.

The coating materials used in conjunction with the present invention areany desired, suitable substances such as defined above with regard toactive ingredients and biologically active ingredients. In someembodiments, the coating materials comprise therapeutic agents, appliedto medical devices alone or in combination with solvents in which thetherapeutic agents are at least partially soluble or dispersible oremulsified, and/or in combination with polymeric materials as solutions,dispersions, suspensions, lattices, etc. The terms “therapeutic agents”and “drugs”, which fall within the biologically active ingredientsclassification described herein, are used interchangeably and includepharmaceutically active compounds, nucleic acids with and withoutcarrier vectors such as lipids, compacting agents (such as histories),virus, polymers, proteins, and the like, with or without targetingsequences. The coating on the medical devices may provide for controlledrelease, which includes long-term or sustained release, of a bioactivematerial. Specific examples of therapeutic or biologically activeingredients used in conjunction with the present invention include, forexample, pharmaceutically active compounds, proteins, oligonucleotides,ribozymes, anti-sense genes, DNA compacting agents, gene/vector systems(i.e., anything that allows for the uptake and expression of nucleicacids), nucleic acids (including, for example, recombinant nucleicacids; naked DNA, cDNA, RNA; genomic DNA, cDNA or RNA in anon-infectious vector or in a viral vector which may have attachedpeptide targeting sequences; antisense nucleic acid (RNA or DNA); andDNA chimeras which include gene sequences and encoding for ferryproteins such as membrane translocating sequences (“MTS”) and herpessimplex virus-1 (“VP22”)), and viral, liposomes and cationic polymersthat are selected from a number of types depending on the desiredapplication. For example, biologically active solutes includeanti-thrombogenic agents such as heparin, heparin derivatives,urokinase, and PPACK (dextrophenylalanine proline argininechloromethylketone); prostaglandins, prostacyclins/prostacyclin analogs;antioxidants such as probucol and retinoic acid; angiogenic andanti-angiogenic agents; agents blocking smooth muscle cell proliferationsuch as rapamycin, angiopeptin, and monoclonal antibodies capable ofblocking smooth muscle cell proliferation; anti-inflammatory agents suchas dexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine, acetyl salicylic acid, and mesalamine, lipoxygenaseinhibitors; calcium entry blockers such as verapamil, diltiazem andnifedipine; antineoplastic/antiproliferative/anti-mitotic agents such aspaclitaxel, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin,cyclosporine, cisplatin, vinblastine, vincristine, colchicine,epothilones, endostatin, angiostatin, Squalamine, and thymidine kinaseinhibitors; L-arginine, its derivatives and salts (e.g., argininehydrochloride); antimicrobials such as triclosan, cephalosporins,aminoglycosides, and nitorfuirantoin; anesthetic agents such aslidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors suchas lisidomine, molsidomine, NO-protein adducts, NO-polysaccharideadducts, polymeric or oligomeric NO adducts or chemical complexes;anticoagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, antithrombin compounds, plateletreceptor antagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, enoxaparin, hirudin, Warafin sodium, Dicumarol, aspirin,prostaglandin inhibitors, platelet inhibitors and tick antiplateletfactors; interleukins, interferons, and free radical scavengers;vascular cell growth promoters such as growth factors, growth factorreceptor antagonists, transcriptional activators, and translationalpromoters; vascular cell growth inhibitors such as growth factorinhibitors (e.g., PDGF inhibitor—Trapidil), growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; Tyrosine kinase inhibitors, chymase inhibitors, e.g.,Tranilast, ACE inhibitors, e.g., Enalapril, MMP inhibitors (e.g.,Ilomastat, Metastat), GP Mafia inhibitors (e.g., Intergrilin,abciximab), seratonin antagonist, and 5-HT uptake inhibitors;cholesterol-lowering agents; vasodilating agents; agents which interferewith endogenous vascoactive mechanisms; survival genes which protectagainst cell death, such as anti-apoptotic Bcl-2 family factors and Aktkinase; and combinations thereof; and beta blockers. In one or moreembodiments, these and other components may be added to a liquid spraycomposition that includes a polymer and a solvent suitable fordissolving all or at least a part of the polymer in the composition.

Modifications to or various forms of the coating materials and/oradditional coating materials for use in coating a medical deviceaccording to the present invention are contemplated herein as would beapparent to one skilled in the art. For example, such coating materialsmay be provided in derivatized form or as salts of compounds.

Polynucleotide sequences useful in practice of the invention include DNAor RNA sequences having a therapeutic effect after being taken up by acell. Examples of therapeutic polynucleotides include anti-sense DNA andRNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA toreplace defective or deficient endogenous molecules. The polynucleotidesof the invention can also code for therapeutic proteins or polypeptides.A polypeptide is understood to be any translation product of apolynucleotide regardless of size, and whether glycosylated or not.Therapeutic proteins and polypeptides include, as a primary example,those proteins or polypeptides that can compensate for defective ordeficient species in an animal, or those that act through toxic effectsto limit or remove harmful cells from the body. In addition, thepolypeptides or proteins that can be incorporated into the polymercoating, or whose DNA can be incorporated, include without limitation,angiogenic factors and other molecules competent to induce angiogenesis,including acidic and basic fibroblast growth factors, vascularendothelial growth factor, hif-1, epidermal growth factor, transforminggrowth factor α and β, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor α, hepatocytegrowth factor and insulin like growth factor; growth factors; cell cycleinhibitors including CDK inhibitors; anti-restenosis agents, includingp15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys,thymidine kinase (“TK”) and combinations thereof and other agents usefulfor interfering with cell proliferation, including agents for treatingmalignancies; and combinations thereof. Still other useful factors,which can be provided as polypeptides or as DNA encoding thesepolypeptides, include monocyte chemoattractant protein (“MCP-1”), andthe family of bone morphogenic proteins (“BMP's”). The known proteinsinclude BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8,BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16.Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6and BMP-7. These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively, or in addition, molecules capable of inducingan upstream or downstream effect of a BMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNA's encodingthem.

Coating materials other than therapeutic agents include, for example,polymeric materials, sugars, waxes, and fats, applied alone or incombination with therapeutic agents, and monomers that are cross-linkedor polymerized. Such coating materials are applied in the form of, forexample, powders, solutions, dispersions, suspensions, and/or emulsionsof one or more polymers, optionally in aqueous and/or organic solventsand combinations thereof or optionally as liquid melts including nosolvents.

When used with therapeutic agents, the polymeric materials areoptionally applied simultaneously with, or in sequence to (either beforeor after), the therapeutic agents. Such polymeric materials employed as,for example, primer layers for enhancing subsequent coating applications(e.g., application of alkanethiols or sulfhydryl-group containingcoating solutions to gold-plated devices to enhance adhesion ofsubsequent layers), layers to control the release of therapeutic agents(e.g., barrier diffusion polymers to sustain the release of therapeuticagents, such as hydrophobic polymers; thermal responsive polymers;pH-responsive polymers such as cellulose acetate phthalate oracrylate-based polymers, hydroxypropyl methylcellulose phthalate, andpolyvinyl acetate phthalate), protective layers for underlying druglayers (e.g., impermeable sealant polymers such as ethylcellulose),biodegradable layers, biocompatible layers (e.g., layers comprisingalbumin or heparin as blood compatible biopolymers, with or withoutother hydrophilic biocompatible materials of synthetic or natural originsuch as dextrans, cyclodextrins, polyethylene oxide, and polyvinylpyrrolidone), layers to facilitate device delivery (e.g., hydrophobicpolymers, such as an arborescent polyisobutylene copolymer, orhydrophilic polymers, such as polyvinyl pyrrolidone, polyvinyl alcohol,polyalkylene glycol (i.e., for example, polyethylene glycol), oracrylate-based polymer/copolymer compositions to provide lubricioushydrophilic surfaces), drug matrix layers (i.e., layers that adhere tothe medical device and have therapeutic agent incorporated therein orthereon for subsequent release into the body), and epoxies.

When used as a drug matrix layer for localized drug delivery, thepolymer component of the coatings may include any material capable ofabsorbing, adsorbing, entrapping, or otherwise holding the therapeuticagent to be delivered. The material is, for example, hydrophilic,hydrophobic, and/or biodegradable, and is preferably selected from thegroup consisting of polycarboxylic acids, cellulosic polymers, gelatin,polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinylalcohols, polyethylene oxides, glycosaminoglycans, polysaccharides,polyesters, polyurethanes, silicones, polyurea, polyacrylate,polyacrylic acid and copolymers, polyorthoesters, polyanhydrides such asmaleic anhydride, polycarbonates, polyethylene, polypropylenes,polylatic acids, polystyrene, natural and synthetic rubbers andelastomers such as polyisobutylene (PIB), polyisoprene, polybutadiene,including elastomeric copolymers, such as Kraton®,styrene-isobutylene-styrene (SIBS) copolymers; polyglycolic acids,polycaprolactones, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polysaccharides such as cellulose, starch, dextran andalginates; polypeptides and proteins including gelatin, collagen,albumin, fibrin; copolymers of vinyl monomers such as ethylene vinylacetate (EVA), polyvinyl ethers, polyvinyl aromatics; other materialssuch as cyclodextrins, hyaluronic acid and phosphoryl-cholines; andmixtures and copolymers thereof. Coatings from polymer dispersions suchas polyurethane dispersions (BAYHDROL, etc.) and acrylic latexdispersions are also within the scope of the present invention.Preferred polymers include polyurethanes; polyacrylic acid as describedin U.S. Pat. No. 5,091,205; and aqueous coating compositions comprisingan aqueous dispersion or emulsion of a polymer having organic acidfunctional groups and a poly-functional crosslinking agent havingfunctional groups capable of reacting with organic acid groups, asdescribed in U.S. Pat. No. 5,702,754. Other polymers that may be usedinclude poly(DL-lactide-co-ε-caprolactone, 80/20) (PLCL), Chronoflex AR(CFR) which is polyurethane 22% solid in dimethylacetamide, andpoly(tetrahydrofurfuryl methacrylate-co-ethyl methacrylate) PTHFMA-EM.

One or more solvents may be used as part of the liquid spray compositionto fully or partially dissolve one or more polymers thereof. Suchsolvents may range from polar solvents (e.g., acetone and methanol) tonon-polar solvents (e.g., tetrahydrofuran and toluene).

Polar solvents, as used herein, are liquids that tend to have higherdielectric constants, where the higher the dielectric constant, thegreater the relative polarity. Such polar solvents may include, forexample, but are not limited to, water, methanol, ethanol, isopropanol,acetonitrile, acetone, and tetrahydrofuran.

Non-polar solvents, as used herein, are liquids that tend to have lowerdielectric constants than polar solvents, where the lower the dielectricconstant, the lower the relative polarity. Such non-polar solvents mayinclude, for example, but are clearly not limited to, toluene,chloroform, hexane, and dichloromethane.

In one or more embodiments herein, particularly where an open matrixcoating is desired, high dielectric constant solvents may be used. Suchhigh dielectric constant solvents include solvents having a dielectricconstant equal to or greater than 10. For example, high dielectricconstant solvents include water (dielectric constant of 80), methanol(dielectric constant of 33), ethanol (dielectric constant of 24), oracetone (dielectric constant of 21).

In one or more other embodiments, low dielectric constant solvents maybe used. Such low dielectric constant solvents include solvents having adielectric constant less than 10. One will recognize that some polarsolvents, such as tetrahydrofuran, are low dielectric constant solventseven though they are polar solvents. For example, low dielectricconstant solvents include tetrahydrofuran (dielectric constant of 7.5),chloroform (dielectric constant of 4.8), or toluene (dielectric constantof 2.4).

The release rate of drugs from drug matrix layers is largely controlled,for example, by variations in the polymer structure and formulation, thediffusion coefficient of the matrix, the solvent composition, the ratioof drug to polymer, potential chemical reactions and interactionsbetween drug and polymer, the thickness of the drug adhesion layers andany barrier layers, and the process parameters, e.g., drying, etc. Thecoating(s) applied by the methods and apparatuses of the presentinvention may allow for a controlled release rate of a coating substancewith the controlled release rate including both long-term and/orsustained release.

The source material held in the source holding apparatus 32 may be anyliquid diluent composition which when provided in combination with theliquid spray composition at the dispensing end 23 of the nozzlestructure results in coating particles being provided in the definedvolume in particle form as described according to the present inventionherein. The source material in source holding apparatus 32 is a liquiddiluent composition that includes at least one of a polar or non-polarsolvent as described herein.

At least in one embodiment, the liquid diluent composition includes oneor more high dielectric constant solvents. Further, at least in oneembodiment, the liquid diluent composition has a high dielectricconstant (i.e., a dielectric constant that is equal to or greater than10). For example, the liquid diluent composition may include a highdielectric constant solvent and include a low dielectric constantsolvent (e.g., mixed solvents), yet still the liquid diluent compositionmay have a high dielectric constant.

Further, when the liquid diluent composition has a high dielectricconstant, the liquid diluent composition may further include an activeingredient, such as a polymer or a drug. Further, at least in anotherembodiment, the liquid diluent Is composition is a high dielectricconstant composition and includes a biologically active ingredient(i.e., without a polymer).

Further, at least in one embodiment, the liquid diluent composition hasa weight concentration of active ingredient that is less than 1 percentof the total weight concentration of the liquid diluent composition(e.g., a biologically active ingredient that is less than 1 percent oftotal weight concentration). Further, in another embodiment, the liquiddiluent composition has a weight concentration of active ingredient thatis less than 0.5 percent of the total weight concentration of the liquiddiluent composition.

Still further, in one embodiment, the liquid diluent composition mayfurther include an additive that is used to control conductivity of theliquid diluent composition. For example, the additive used to controlconductivity may include a buffer solution such as a phosphate buffer(e.g., for spraying particles including peptides), an acid such asnitric acid, or a salt such as ammonium chloride. Generally, with use ofa low dielectric constant solvent, an additive to increase theconductivity of the liquid diluent composition is needed to apply anopen matrix coating.

Still further, at least in one embodiment, the liquid diluentcomposition includes only solvents and has a high dielectric constant(e.g., includes at least one high dielectric constant solvent. With useof only solvents in the liquid diluent composition, fouling of the spraytip is less likely.

The coatings of the present invention are applied such that they resultin a suitable thickness, depending on the coating material and thepurpose for which the coating or coatings are applied. For example,coatings applied for localized drug delivery are typically applied to athickness of at least about 1 micron and not greater than 30 microns. Inone embodiment, the thickness is greater than 2 microns. Further, inanother embodiment, the thickness is not greater than 20 microns. Inaddition, very thin coatings such as those as thin as 100 Angstroms maybe provided. Much thicker coatings of more than 30 microns are alsopossible.

Several detailed configurations for the dispensing device 19 aredescribed in further detail herein. For example, FIG. 7A is a moredetailed diagram of one configuration of a portion 300 of anelectrospraying apparatus such as shown generally in FIG. 1 including adual concentric opening dispensing device 314 extending along axis 301according to the present invention from a first end 304 to a second endor dispensing end 380. First end 304 may be formed of conductiveportions to facilitate application of voltages or ground to capillarytube 320.

The first end 304 includes a distributor head 316 that is coincidentwith axis 301 for use in establishing the spray of particles. Thedistributor head 316 includes capillary tube 320 having an axistherethrough coincident with axis 301. The capillary tube 320 includes afirst end 330 sealingly positioned in aperture 385 of the first end 304by conductive sealing element 337 at the upper surface 383 of the firstend 304. The capillary tube 320 further includes a second end 332positioned for providing a liquid spray composition to the dispensingend 380 (i.e., through an inner opening 391 that terminates at thedispensing end 380 for use in generating the spray of particles asdesired). The capillary tube 320 may be made of any suitable material,such as, for example, platinum, silica, stainless steel, etc. and may beof any suitable size. For example, the capillary tube may, at least inone embodiment, have an outer diameter in the range of about 8 μm toabout 2.5 mm, and an inner diameter in the range of about 6 μm to about2 mm. Further, in another embodiment, the inner diameter of thecapillary tube is in the range of about 10 μm to about 200 μm.

Further, the distributor head 316 includes a nozzle portion or casing322 which as illustrated in FIG. 7A is an elongate substantiallycylindrical metal casing concentric with the capillary tube 320 forproviding an outer opening 392 concentric with inner opening 390 forproviding liquid diluent compositions to the dispensing end 380.However, the casing 322 can be conductive or nonconductive. Together, inthis particular embodiment, the capillary tube 320 and the casing 322form the dual opening capillary tube electrode of the distributor head316 for use in providing the spray of particles when operating in a conejet mode. The casing or nozzle portion 322 includes a first end portion336 which tapers at section 335 thereof to a narrower second end portion338. The second end portion 338 extends from the tapered section 335 andis concentric with the second end 332 of the capillary tube 320. Thenarrow end of the tapered section 335 extends a distance of about 5 mmto about 5 cm from the lower surface 385 of the first end 304. The outerdiameter of the second end portion 338 is in the range of about 2 mm toabout 5 mm and the inner diameter of the second end portion 338 is inthe range of about 0.1 cm to about 0.2 cm. The second end 332 of thecapillary tube 320 extends beyond the second end portion of the metalcasing or nozzle portion 322 towards the target surface to be coated bya distance of about 2 mm to about 5 mm. The nozzle portion 322 is formedof any suitable metal or nonconductive material such as stainless steel,brass, alumina, or any other suitable material. The nozzle portion 322is spaced from the capillary tube 320 by spacers 326 or other spacingstructures. For example, a metal casing 322 may be deformed atparticular portions, such as pin points or depressions, to create a neckfor centering the capillary tube 320 therein. An inlet 348 is configuredfor directing the liquid diluent composition 349 in aperture or opening392 between the concentric capillary tube 320 and the nozzle portion322. One will recognize the capillary tube electrode may take one ofmany configurations.

A gas inlet 354 is provided in the first end 304 to allow for input of astream of electro-negative gases, e.g., CO₂, SF₆, etc., to form a gassheath about the capillary tube 320 or flood the region about dispensingend 380. This gas sheath allows the applied voltage to be raised tohigher levels without corona discharge, e.g., the electrostaticbreakdown voltage for the capillary tube electrode is increased. Theentire portion of end 304 or portions thereof may be formed ofconductive materials to facilitate application of a voltage or ground tothe capillary tube electrode. For example, sealing elements 337 may benonconductive, but in one embodiment are conductive to facilitateapplication of a voltage or ground to capillary tube 320. Further, inone or more embodiments, generally, the region around the capillary tube320 and the nozzle portion 322 is flooded with a gas through the port354 to increase the electrostatic breakdown voltage for the capillarytube electrode. In one embodiment, a chamber in which the coatingprocess is being completed is flooded with the gas through the port 354and then a flow in the range of about 5 cc/min to about 200 cc/min iscontinued through the port 354.

To establish the spray of particles from the dual opening dispensingdevice 314, a first flow of a liquid spray composition is received inthe first end 330 of the capillary tube 320 and flows through opening391. For example, the flow rate of the liquid spray composition may begreater than about 0.01 μl/min or less than about 10 μl/min; or furthermay be less than about 5 μl/min, or even less than about 3 μl/min.Further, a second flow of a liquid diluent composition 349 is receivedin the port 348 of the nozzle and provided to opening 392. For example,the flow rate of the liquid diluent composition may be greater thanabout 0.01 μl/min or less than about 10 μl/min; or further may be lessthan about 5 μl/min.

In one embodiment, a relatively high voltage, for example, in the rangeof about 2000 volts to about 6000 volts, may be applied between theobject being coated and the capillary tube 320 to establish thepotential difference between the first and second electrode of thespraying apparatus and cause operation in cone-jet mode. In thisparticular illustrative configuration, capillary tube 320, metal casing322, and sealing element 337 are conductive. Spray 328 is establishedforward of the dispensing tip 380 of the second end 332 of the capillarytube 320 per a mode of operation as previously described. The potentialdifference between the electrodes establishes an electric field therebetween, causing operation in a cone-jet mode for generation of coatingparticles according to the present invention.

The electrospray coating system 10 illustrated and described generallyherein with reference to FIG. 1 can be controlled to provide forparticular types of selected coatings according to the presentinvention. For example, one or more different parameters of the system10 may be controlled so as to form an open matrix coating as opposed toa closed film coating.

According to one or more embodiments of the present invention, thecoating process using one or more controlled parameters as describedherein allows for applying nanocomposite coatings onto objects such ascoronary stents and/or other medical devices. The cone-jet mode ofoperation produces highly charged, uniform, monodisperse nanoparticlescomprised of one or more components that are used to coat the object.Non-line-of-sight coating can be achieved (i.e., coating of surfaces notdirectly in the line of sight of the dispensing end 23, such as theinterior surface of a stent). The coating particles in suchnon-line-of-sight coating are directed to the surface of the objectbeing coated by the established electrical field, which aids in theuniform coating of objects with intricate architecture. Use of the dualopening nozzle structure (e.g., a dual-capillary spray head) permits twoliquid streams of materials to be mixed at the spray tip or dispensingend 23, which enables the application of multiple agents in ananocomposite open matrix coating and the co-spraying of materials whichare otherwise incompatible. The electrospray process can accommodate arange of polymers and solvents that are used or likely to be used incoating objects such as stents.

In at least one embodiment, solvents required to dissolve a polymer(e.g., poly(isobutylene), poly(styrene-b-isobutylene-b-styrene, etc.) tobe sprayed are low dielectric constant non-polar solvents (e.g.,toluene) or are low dielectric constant polar solvents (tetrahydrofuran)and not easily amenable to electrospray. However, using the followingtechniques including, for example, adding a higher dielectric constantsolvent such as methanol in the inner or in the outer capillary liquidstream, as further described herein, a liquid spray composition thatincludes such a hard to spray dissolved polymer can be used to coat anobject.

Generally, one or more control parameters may be useful in selecting atype of coating to be formed on the object 15. Such control parameterswhich shall be discussed in further detail herein include controlling aflow rate of the second flow of the liquid diluent composition in theouter opening 29 relative to a flow rate of the first flow of the liquidspray composition in the inner opening 27 (e.g., controlling the ratioof the flow of the liquid diluent composition to the total flow of theliquid spray composition and liquid diluent composition dispensed at thedispensing end 23), selecting a particular liquid diluent composition tobe provided in the outer opening 29 (e.g., selecting a particular liquiddiluent composition having a particular conductivity); and controllingthe evaporation process of the microdroplets dispensed from thedispensing end 23 of the nozzle structure 18.

The relative flow rate of the second flow of the liquid diluentcomposition in the outer opening 29 to the flow rate of the first flowof the liquid spray composition in inner opening 27 can be selected toachieve a desired coating described herein. For example, selection of ahigher ratio of flow rate for the liquid diluent composition relative tothe total flow rate of the liquid spray composition and liquid diluentcomposition dispensed at the dispensing end 23, may result in theformation of a closed film coating.

As would be recognized, the ratio necessary to achieve a desiredselected coating may depend on the compositions being used. However,generally, according to the present invention as the flow rate of theliquid diluent composition in the outer opening 29 exceeds 5 times theflow rate of the liquid spray composition in the inner opening 17, aclosed film coating occurs. In other words, as the ratio of flow ratefor the liquid diluent composition at the outer opening 29 relative tothe total flow rate of the liquid spray composition and liquid diluentcomposition dispensed at the dispensing end 23 gets closer to 1, aclosed film coating is achieved. As such, a user with the desiredcompositions known, can adjust the flow rates to achieve a selected typeof coating by controlling the flow rate of the second flow of the liquiddiluent composition in the outer opening 29 relative to the flow rate ofthe first flow of the liquid spray composition in inner opening 27.

Selecting a particular liquid diluent composition to be provided in theouter opening 29 can also be used to achieve a desired coating describedherein. For example, selecting a liquid diluent composition thatincludes one or more high dielectric constant solvents (e.g., such as aliquid diluent composition that includes at least one of acetone ormethanol (both higher dielectric constant solvents)) such that theliquid diluent composition has a high dielectric constant is likely toresult in an open matrix coating. Likewise, selecting a liquid diluentcomposition that includes one or more low dielectric constant solvents(e.g., such as a liquid diluent composition that includes at least oneof chloroform, toluene, or tetrahydrofuran (all low dielectric constantsolvents)) such that the liquid diluent composition has a low dielectricconstant is likely to result in a closed film coating.

In other words, selecting a liquid diluent composition for the outeropening that has a certain dielectric constant can be used to achieve aparticular selected coating. For example, liquid diluent compositionsthat have a high dielectric constant (i.e., greater than 10) aretypically required to obtain an open matrix coating.

Yet further, at least in one embodiment, selecting a particular highdielectric constant solvent for use in the liquid spray composition tobe provided in the inner opening 27 may also be used to achieve adesired coating described herein. For example, selecting a solvent foruse in the liquid spray composition that includes one or more highdielectric constant solvents (e.g., such as a liquid diluent compositionthat includes at least one of acetone or methanol (both higherdielectric constant solvents)) may be beneficial in providing an openmatrix coating. For example, such a high dielectric constant solvent maybe added to a low dielectric constant solvent that is required todissolve a particular polymer to provide the ability to apply an openmatrix coating (e.g., making the dielectric constant of the liquid spraycomposition higher).

Yet further, increasing the conductivity of the second flow of theliquid diluent composition is useful for achieving an open matrixcoating on the at least one surface of the object 15. Such conductivitymay be achieved by selecting, at least in one embodiment, a liquiddiluent composition that has a conductivity greater than 1 μS cm⁻¹(microSiemen/cm). In another embodiment, a liquid diluent compositionthat has a conductivity greater than 6.8 μS cm⁻¹ is beneficial informing an open matrix coating.

Use of a liquid diluent composition that has a conductivity greater than1 μS cm⁻¹, or even greater than 6.8 μS cm⁻¹, provides for substantiallyround particles being formed in the open matrix coating. Suchsubstantially round particles are shown in FIG. 10 c,d,g,h, as opposedto elongated fiber particles shown in FIGS. 10 a,b,e,f. Thesubstantially round particles are a direct result of using a highconductivity liquid diluent composition in the outer opening.

The conductivity of the liquid diluent composition can be manipulatedusing any known techniques. The liquid diluent composition may include asingle component having a relatively high conductivity or a relativelyhigh conductivity component may be added to a relatively lowconductivity component. For example, an acid (e.g., nitric acid) or asalt (e.g., ammonium chloride) may be used to increase the conductivityof certain types of solvents (e.g., acetone, methanol, or water) thatare desired for use as part of the liquid diluent composition.

At least in one embodiment, a lower conductivity liquid spraycomposition is provided at the inner opening 27. For example, theconductivity of the liquid spray composition (e.g., including de-ionizedwater and toluene) may be in the range of about 0.3 μS cm⁻¹ to about 1.0μS cm⁻¹. In such a case, a liquid diluent composition (e.g., such asthat including nitric acid) having a conductivity in the range of about100 μS cm⁻¹ to about 1000 μS cm⁻¹ may be necessary to facilitate breakupof the inner stream of liquid spray composition so as to spray thecoating particles.

At least in one embodiment, the liquid spray composition includes atleast a biologically active material and a polymer. For example, in oneor more embodiments, the ratio of weight concentrations of polymer tobiologically active material (e.g., polymer:dexamethasone) may be ashigh as 10:1 or as low as 5:1. However, even lower ratios may besprayed. Further, in one or more other embodiments of the liquid spraycomposition, the weight concentration of the active ingredient (e.g.,the polymer or the polymer and biologically active ingredient) may beless than 5 percent of the total weight of the liquid spray composition,and may be less than 1 percent of the total weight concentration of theliquid spray concentration.

Further, the evaporation process of the microdroplets dispensed from thedispensing end 23 of the nozzle structure 18 may be controlled toachieve a particular selected coating. For example, the time allowed forevaporation of the microdroplets may be controlled as a function ofselected type of coating to be applied.

In one embodiment, the time allowed for evaporation of the microdropletsbefore they reach the object 15 to form a coating thereon is increasedso that an open matrix coating can be formed. For example, as shown inFIG. 4, a dual opening nozzle structure 120 is shown that has adispensing end 122. The distance between the dispensing end 122 of thenozzle structure 120 and the surface 13 of the object 15 to be coated iscontrolled depending on the selected type of coating to be applied. Forexample, the distance d between the dispensing end 122 of the nozzlestructure 120 and the surface 13 of the object 15 may be increased uponselection of an open matrix coating to allow more time of flight forevaporation of the microdroplets or decreased upon selection of a closedfilm coating to allow less time for evaporation. As would be recognize,either the nozzle structure 120 or the object 15 may be moved to adjustthe distance d.

As described above, as the microdroplets evaporate, the charge of themicrodroplets concentrates on the active ingredients resulting in aspray of charged particles. In one embodiment, the coating system 10 isconfigured such that prior to contact with the at least one surface 13of the object 15, the weight percent of solvent in the evaporatedmicrodroplet is less than 85% (e.g., corresponding to a weight percentof 15% polymer in a droplet that only includes only polymer solids andthe solvent). At least in one embodiment, some solvent component forms apart of the particle volume as the particle contacts the surface 13 ofthe object 15. With some solvent component being a part of the residualparticle volume occupied by the evaporated microdroplet, adhesion of themicrodroplet (including the particle) to the surface 13 of the object 15may be enhanced. After the microdroplet has contacted the surface 13 ofthe object 15, the remainder portion of the solvent evaporates, leavingthe particle coated on the surface 13 of the object 15.

Generally, at least in one embodiment, an open matrix coating isfacilitated by solvent evaporation such that the residual solventimmediately prior to contact with the at least one surface 13 of theobject 15 is less than 85% by weight of the evaporated microdroplet.However, the relative composition of solvent:polymer in the particlethat promotes open matrix formation may be different depending on thepolymer used. But, generally, at least in one embodiment, an open matrixcoating would be facilitated by solvent evaporation such that theresidual solvent prior to contact with the at least one surface 13 ofthe object 15 is less than 80% by weight of the evaporated microdroplet.Likewise, generally, at least in one embodiment, a closed film coatingwould be facilitated by solvent evaporation such that the residualsolvent immediately prior to contact with the at least one surface 13 ofthe object 15 is more than 90% by weight of the evaporated microdroplet.It will be apparent to one skilled in the art that the relativepercentages of solvent and polymer that are given may vary according tothe characteristics of the specific polymer that is used.

The amount of evaporation prior to the microdroplet/particle contactingthe surface 13 of the object 15 may be controlled in a number ofdifferent ways for applying one or more different selected types ofcoatings, in addition to selecting a distance d as shown in FIG. 4. Forexample, the evaporation may be controlled by the type of solvent used,the temperature and pressure of a chamber in which the medical device isprovided, the size of the microdroplet, the humidity, etc.

For example, maintaining a temperature in the defined volume in therange of 20 degrees centigrade to 30 degrees centigrade may be necessaryupon selection of an open matrix coating. The temperature typicallyshould not exceed the glass transition temperature for a given polymer.

Further, in one embodiment, maintaining humidity in the defined volume17 to less than 20 percent RH assists in maintaining stability of thecoating process. Controlling relative humidity prevents arcing or coronadischarge. If the relative humidity is kept lower, higher voltages canbe used before corona discharge becomes a problem, facilitating the conejet formation and maintenance.

As shown in FIG. 5, evaporation may also be controlled by providing agas stream 130 in proximity to the cone-jet formed at the dispensing end134 of a nozzle structure 132. As stream of gas along side the nozzlestructure 132 may be provided, or the defined volume may be flooded witha gas. For example, one or more gases such as nitrogen or carbon dioxidemay be used to increase evaporation. As such, with increasedevaporation, achieving an open matrix coating is more likely. Yetfurther, providing the gas stream may assist in keeping the cone-jetstable (e.g., provide anti-fouling of the dispensing end 23). Stillfurther, the gas stream should not generate turbulence around the conejet, as this could cause instability thereof.

As previously mentioned, as the microdroplets evaporate and charge isconcentrated on the particles, the nonuniform electric field providesfor containment of particles and/or direction for the particles whichwould otherwise proceed in random directions due to the space chargeeffect; the space charge effect being necessary to provision ofmonodisperse and nonconglomerated particles. The space charge effect isgenerally dependent upon the size of the particles and the chargethereon. With the electric field being utilized to move the particlestowards the object 15 and preventing them from scattering to otherlocations, the amount of coating material necessary to coat the object15 is substantially reduced.

The loop electrode 40 as shown in FIG. 4 can also be used to preventscattering and decrease the amount of coating material necessary to coatthe object 15. For example, the loop electrode 40 can be used toestablish the nonuniform electric field when positioned along a planegenerally orthogonal to an axis 128 along which the nozzle structure 120extends. The position, size and shape of the loop can be used to controlthe direction of the coating particles so as to coat the desiredsurfaces of the object 15. Generally, the loop 40 may be provided at adistance 126 that is about 1 mm from the target object 15 or may befurther away from the target object. For example, the loop may be as farfrom the target as possible but still capable of generating the desirednon-uniform electric field. For example, the loop 40 may lie inapproximately the same plane as the tip of the nozzle structure (e.g.,orthogonal to the axis along which the nozzle structure extends).

Yet further, one or more process techniques may be implemented tomaintain a stable cone-jet during operation of the coating process so asto achieve the selected type of coating. For example, such techniquesmay include adjusting the voltage between the dispensing end of thenozzle structure 18 and the object 15 being coated as the thickness ofthe selected type of coating increases so as to maintain a stablecone-jet at the dispensing end 23 of the nozzle structure 18 and/ormonitoring at least one characteristic associated with the cone-jet todetermine the stability of the cone-jet based thereon, and thereafteradjusting one or more process parameters to maintain a stable cone-jet.

When the thickness of the selected type of coating 105 increases on theobject 15, the cone-jet may become unstable. For example, as the coatingthickness increases, the electrical potential between the first andsecond electrode of the system 10 may no longer be sufficient tocontinue cone-jet mode operation. As such, adjusting the voltage betweenthe dispensing end 23 of nozzle structure 18 and the object 15 beingcoated may be needed to maintain a stable cone-jet at the dispensing endof the nozzle structure 18. The adjustment of the voltage may be donemanually by a user or may be performed automatically as a function ofone or more characteristics of the cone-jet as described further herein.

For example, as illustratively shown in FIG. 1, a detection apparatus 50(e.g., an imaging apparatus) may be used to detect at least onecharacteristic associated with the cone-jet (e.g., shift in angle 104 asshown in FIG. 2C). The stability of the cone jet may then be determinedbased on the at least one characteristic and one or more processparameters may be adjusted accordingly to maintain a stable cone-jet. Inother words, at least in one embodiment, an imaging apparatus may beused to detect the angle 104 as shown in FIG. 2C associated with thecone-jet. Depending on the desired angle 104 for maintaining stability,control apparatus 55 may determine that the cone-jet is on the verge ofinstability (e.g., due to increased thickness of the coating 105 beingformed on the object 15). Upon such a determination, the electricalpotential between the dispensing end 23 and the object 15 may beincreased to maintain stable cone-jet operation.

Yet further, other characteristics associated with the cone-jet may bemonitored. For example, the detection apparatus 50 may detect one ormore flutters in the cone-jet (e.g., the cone-jet going into pulsatingmode temporarily from cone-jet mode). Further, the detection apparatusmay use imaging of the cone-jet to detect bubbles in at least one of theliquid flows being provided thereto. If bubbles are detected or fluttersare detected, one or more various actions may be taken. For example, theflow of liquid to the nozzle may be modified, the flow may beinterrupted to prevent sputtering on the surface of the target, and/orthe voltage may be adjusted to eliminate the instability of thecone-jet.

One will recognize that more than two concentric openings may beprovided which terminate at the dispensing end 23 of the nozzlestructure 18 (e.g., to provide more than two flows of compositions atthe dispensing end). For example, although any suitable number ofopenings may be used, FIG. 6 shows a nozzle structure 150 that includesthree concentric openings that terminate at the dispensing end 151 andwhich lie along axis 161. One will recognize that the termination ofsuch openings can be displaced from one another along the axis 161 butmust be in close proximity to allow the cone-jet to form from allcompositions provided at the termination of such openings.

As shown in FIG. 6, inner opening 152 is provided along axis 161, andouter opening 154 is formed concentric therewith. An intermediateopening 153 is provide therebetween. At least in one embodiment, abiologically active material is provided in a liquid composition to theinner opening 152, a polymer at least partially dissolved in a solventis provided to the intermediate opening 153, and a liquid diluentcomposition is provide to the outer opening 154. In cone-jet operation,a spray of coated particles is formed for coating an object 15. Forexample, at least in one embodiment, the coated particles may includebiologically active material encapsulated by the polymer.

FIG. 7B is a more detailed diagram of an alternate exemplary capillaryelectrode configuration 400 for the distributor head 316 of FIG. 7Awhich includes the ability to spray particles from three flows of threedifferent liquid compositions. Like reference numbers are used in FIG.7B for corresponding like elements of FIG. 7A to simplify description ofthe alternate capillary configuration 400.

The capillary electrode configuration 400 includes a first capillarytube 412 having an axis coincident with axis 301 for receiving a firstflow of a liquid spray composition from a source, e.g., a suspension ofbiologically active material, such as a drug. Further, a secondcapillary tube 414 is concentric with the first capillary tube 412. Anannular space 487 between the inner and outer capillaries 412, 414 isused to receive a second flow of a liquid spray composition (e.g., apolymer dissolved in a suitable solvent) and provide the flow to thedispensing tip 495 for use in establishing the spray forward thereof Inmore detail, the housing portion 430 includes an aperture 483 extendingfrom a first end 480 of the housing portion 430 to a second end 482thereof. An inlet port 420 opens into the aperture 483. The inlet port420 receives the second flow of liquid spray composition 422 to bedirected in the annular space 487 about the capillary tube 412.

The first capillary tube 412 has a first end 413 and a second end 415.The capillary tube 412 is positioned in the aperture 483 of the housingportion 430 of generally T-shaped configuration. The first end 413 ofthe capillary tube 412 is sealed to housing 430 using conductive element431 at the first end 480 of the housing portion 430. The capillary tube412 extends from the second end 482 of the housing portion 430 and withthe second capillary tube 414 forms the annular space 487.

The second capillary tube 414 includes a first end 490 and a second end491. The second capillary tube 414 is positioned so that it isconcentric with the first capillary tube 412. The first end 490 of thesecond capillary tube 412 is coupled to the second end 482 of thehousing portion 430 using conductive element 432. Further, the secondend 491 of the second capillary tube 414 is held in place relative tothe nozzle portion 322 by spacers 326. The second capillary tube 414extends beyond the first capillary tube 412 a predetermined distance inthe direction of the target surface to be coated; about 0.2 mm to about1 mm. The portion of the second capillary tube 414 at the dispensing tip495 which extends beyond the first capillary tube is tapered at a 60degree to 75 degree angle for obtaining stable spray pattern andoperation mode, e.g., consistent spraying patterns.

Further, the second capillary tube 414 extends beyond the second end 338of the nozzle portion 322 a predetermined distance (d5), about 2 mm toabout 5 mm. The first capillary tube 412 has diameters like that ofcapillary tube 320 of FIG. 7A. The second capillary tube concentric withthe first capillary tube has an outer diameter of about 533.4 μm toabout 546.1 μM and an inner diameter of about 393.7 μm to about 431.8μm. The gap d6 at the tip of the second capillary tube 414 is in therange of about 10 μm to about 80 μm. The other configuration parametersare substantially equivalent to that described with reference to FIG.7A. In such a configuration, dual streams of liquid spray compositionsare provided for establishing a spray from dispensing tip 495 of theapparatus. However, further, a third liquid diluent composition 349 isalso provided through inlet port 348 to dispensing tip 495.

Clearly, the present invention is not limited to the use ofcapillary-type nozzle structures as various suitable nozzle structuresmay be employed. For example, any nozzle structure suitable to provide aspray of particles according to the principles described herein may beused, e.g., slits that may provide various cone-jets, nozzle structureshaving portions thereof that are integral with portions of other nozzlestructures, nozzle structures that form a part of a chamber wall,radially or longitudinally configured slots, or other multiple openingnozzle structures (e.g., micromachined nozzle structures that have dualor triple openings), etc.

Yet further as would be recognized by one skilled in the art multiplenozzle structures may be used to increase coating capacity according tothe present invention. For example, as shown in FIG. 8, an electrospraycoating system 180 employs a dispensing apparatus 182 to establish oneor more sprays of particles 184 (e.g., sprays of microdroplets whichevaporate to form sprays of coating particles). The dispensing apparatus182 includes a plurality of nozzle structures 188 which operate in amanner like that of nozzle structure 18 as shown in FIG. 1 to provide aselected type of coating 105 on surface 13 of object 15 positioned in adefined volume (shown generally by the dashed line 190).

EXAMPLES SETUP

The examples to follow were carried out to produce nanocompositecoatings on surfaces with intricate architecture using an electrosprayprocess that generates nanoparticles, initially focusing on coronarystents, and quantifying their physical characteristics. Further, theexamples were carried out to achieve a level of reproducibility andperformance of surface coatings. Yet further, the examples were carriedout to:

-   1. Assess the relative importance of multiple coating process    parameters on achieving the type of coating desired where outcome    measures included coating weight, coating characteristics, and    voltage required to maintain a stable cone-jet for each set of    conditions including:    -   a. Feed rate and composition of polymer, drug and solvent    -   b. Polymer and drug concentration in sprayed material    -   c. Conductivity of spray fluids    -   d. Distance between spray tip and target-   2. Using optimized process parameters, apply consistent coating    weights to the surface of a coronary stent for one or more polymers,    where the target weight of coating was between 400 and 600 μg for    polymer and drug combined.-   3. Determine the transfer efficiency for each coating, defined as    the ratio of the coating weight to the mass of solid material    sprayed.-   4. Determine coating thickness using tangential cryomicrotomy and    scanning electron microscopy and profilometry.-   5. Determine coating characteristics, surface uniformity, and    adherence of each coating type before and after balloon expansion of    the stent.-   6. Determine the uniformity of the drug/polymer matrix exploring    other possibilities including atomic force microscopy and FTIR    microscopy.-   7. Determine the stability of biodegradable coatings under high    ambient humidity.

COATING REAGENTS USED IN THE EXAMPLES

For the primary coating experiments, conducted to determine coatingconsistency and to optimize process-control variables, we selectedpolymers available on the market that represented a range of potentialcoating materials, from biodegradable materials to drug-elutingmaterials. The required solvents to dissolve these polymers ranged fromsolvents with higher dielectric constants (e.g., acetone and methanol)to solvents with lower dielectric constants (e.g., tetrahydrofuran andtoluene).

The majority of experiments were made using two polymers:Poly(DL-lactide-co-ε-caprolactone, 80/20) (PLCL), inherent viscosity0.77 dL/g in chloroform, is a biodegradable polymer that was availablefrom Absorbable Polymers International, Pelham, Ala., USA; andChronoflex AR (CFR) is polyurethane 22% solid in dimethylacetamide. CFR,a drug-eluting material, is available from CardioTech International,Wilmington, Mass., USA.

Solvents used for these various polymers included acetone, chloroform,tetrahydrofuran (THF), methanol (solvents were HPLC grade) and phosphatebuffer, pH 7.4, all available from Sigma-Aldrich, St. Louis, USA. Wealso conducted exploratory spray experiments with two additionalpolymers, poly(isobutylene) (PIB) and poly(tetrahydrofurfurylmethacrylate-co-ethyl methacrylate) PTHFMA-EM, also available fromSigma-Aldrich.

Initially three drugs were proposed for use in the coatings:dexamethasone, rapamycin and paclitaxel; e.g. see Ranade et al (2004).In the course of these studies, we sprayed both dexamethasone andpaclitaxel successfully. The samples produced during these experimentswere going to be analyzed on multiple shared instruments at theUniversity of Minnesota. Because of the potential toxicity of rapamycinand paclitaxel and the possibility of contaminating the sharedinstruments, we elected to conduct the characterization studies usingdexamethasone as the primary drug agent. Dexamethasone (99% purity) wasavailable from Alexis Biochemicals, San Diego, Calif., USA.

Solutions of polymers were prepared at different concentrations asdetermined by the spraying conditions. A variety of polymerconcentrations and solvent combinations were investigated; acceptableconcentrations (weight/volume) and primary solvents included PLCL 5% inacetone or a blend of acetone and chloroform, CFR 2% in THF or a blendof THF and methanol, PIB 1% in THF, and PTHFMA-EA 2% in THF, e.g. seeAlexis et al (2004), Puskas et al (2004), Szycher et al (2002), andVerhoeven et al (2004). Dexamethasone was added to polymer solutions,with final concentrations varying from 10% to 20% of the polymer weight,resulting in a 10:1 polymer:dexamethasone ratio by weight. Conductivityof solvent solutions was adjusted to appropriate ranges, typically byadding μl quantities of concentrated nitric acid, measured using a OrionBenchtop Conductivity Meter, model 555A with probe M (Thermo ElectronCorp., Waltham, Mass., USA).

The optimal spray solvent for each polymer was determined by comparingthe various solvents specified as compatible with each polymer by themanufacturer and assessing spray performance in terms of ability to forma stable cone-jet (i.e., stable dark tip appearance, no flutteringbetween cone-jet and non-cone-jet mode, and no corona discharge, seeFIG. 2C herein). A stable cone-jet is required to maintain uniformity ofparticle size during the spray process. Likewise, optimal feed rateswere determined by evaluating the voltage required to generate a stablecone-jet spray mode while, at the same time, visually inspecting thetarget for obvious flaws such as spatter marks on the surface that wereseen when the cone-jet was disrupted. This process produced a set ofvoltages and feed rates for each polymer and solvent combination thatwere compatible with electrospray operation in the cone-jet mode.

TARGETS USED FOR COATING EXAMPLES

Originally both stainless steel springs made of 316 stainless steel, andstents made from the same material were to be used. While we did makesome use of the springs in our initial process development work, it wasdetermined that stents should be used. Generic stents that could beexpanded in diameter 3-fold by balloon were obtained (Pulse Systems,Concord, Calif., USA). These were fabricated from 316 stainless steelthat was annealed and electropolished. Dimensions were 12 mm in length,1.57 mm in outer diameter and 1.30 mm in inner diameter, a size andgeneral configuration that is equivalent to stents in current use.

Because some of the coating characterization tools could not be used toassess a rounded surface, flat stainless steel plates were used for someaspects of coating development. One cm-square pieces were pressed from30.5 cm-square mirror-finished 316 stainless steel sheets 0.79 mm thick(McMaster Carr, Chicago, Ill., USA). For coating experiments, thecoating was sprayed on the mirror-finished side of the small cut pieces.

Electrospray Coating Apparatus

Two electrospray systems were used in these experiments. One system,which had a fixed target, was used to explore optimum spray conditions.The second system, which had a movable spray target platform, was usedas the primary stent-coating apparatus. The spray head in both of thesesystems was a custom-manufactured dual capillary design, in which eachcapillary was fed by external syringe pumps (Harvard Apparatus,Holliston, Mass., USA). A high-voltage power supply (Bertan Associates,Hicksville, N.Y., USA) was used to apply voltage to the spray tip,typically over a range of 3.5-5.5 kV at ˜2.5 mA. The target was movedinto position by a motor-driven, computer-controlled, movable stage thatpermitted vertical and horizontal adjustments in positioning the targetwith respect to the spray tip as well as a variable advancement rate ofthe target through the spray field. The spray operation was imaged usinga video inspection microscope (Panasonic) that produced real-time imagesof the spray tip as well as the target. The spray operation wascontained within a negative-pressure chamber that drew gas supply (air,nitrogen or carbon dioxide) through a filtered supply line and wasvented through a filter and fume hood. Temperature and relative humiditywere monitored continuously.

Unless otherwise indicated, the spray apparatus used to coat objects byelectrospray was equivalent to that shown in and described withreference to FIG. 7A. The apparatus included a dual concentric openingdispensing device 314 extending along axis 301. First end 304 was formedof conductive portions to facilitate application of voltages or groundto capillary tube 320. The capillary tube 320 was formed of stainlesssteel and had an outer diameter of 560 μm and an inner diameter of 260μm. Further, the distributor head 316 included a nozzle portion orcasing 322 that was an elongate substantially cylindrical metal casingconcentric with the capillary tube 320 for providing an outer opening392 concentric with inner opening 391 of the capillary tube 320. Thecasing or nozzle portion 322 included a first end portion 336 whichtapered at section 335 thereof to a narrower second end portion 338. Thesecond end portion 338 extended from the tapered section 335 and isconcentric with the second end 332 of the capillary tube 320. Thedistance from the end of the tapered section 335 to the end of the metalcasing 322 is about 4.7 mm. The outer diameter of the second end portion338 is about 1050 μm and the inner diameter of the second end portion338 is about 680 μm. The second end 332 of the capillary tube 320extends beyond the second end portion of the metal casing or nozzleportion 322 towards the target surface to be coated by a distance ofabout 5 mm.

The dispensing device was constructed of various materials. Primarily,the conductive elements (e.g., element 316) were constructed ofstainless steel, the apparatus was used in a chamber made of plexiglass,and insulative parts (e.g., element 383) thereof were made of a plastic,black delrin, material.

The electrospray was operated in a cone-jet mode with a flow of 4000cc/min flow of N₂ through port 354 and about the same amount exhaustedfrom the coating system.

Determining Optimal Spray Operating Parameters

A Design of Experiment (DOE) approach was taken to setting up theexperimental conditions and evaluating the impact of the various processparameters (e.g., see DOE Simplified: Practical Tools for EffectiveExperimentation. Anderson M J and Whitcomb P J. Productivity, Inc., NewYork, N.Y. 2000). Using this approach, a matrix of different operatingconditions was established and used to spray the flat stainless steelsquares described herein. Parameters evaluated included polymerconcentration, drug concentration, conductivity of the solutions, sprayfeed rates, and spray distance to target. Outcome variables recordedincluded voltage, stability of the cone jet spray mode, coating weight,and the surface qualities of the coating under SEM imaging. Results ofthese experiments were used to guide the selection of initial operatingparameters for the stent-coating experiments.

Coating Weight

For each coating, at least 10 to 12 individual stents were sprayedconsecutively. Coating weight was determined by weighing the spraytarget before and after spraying using a Cahn electrobalance, Model 21.A goal was to achieve coatings of approximately 500 μg per stent;however, we also conducted some spray experiments where very thincoatings of approximately 40 μg were applied, or where we coated onlycertain regions of the stent, for a coating weight of approximately 30μg.

Transfer Efficiency

Transfer efficiency is defined as the ratio of the mass of solidmaterial sprayed to the weight of the coating. Only the weight ofcoating on the target stent was determined; the weight of material thatadhered to the spray fixture was not used in the calculation due to theinability to weigh the much larger fixture reliably. Most likely theportion of sprayed material that was not present on the stent wascaptured by the fixture due to the force of attraction generated by thestrong electrical field.

Coating Uniformity

Stents were imaged using light and scanning electron microscopy (SEM) toverify coating qualities, surface uniformity, and lack of void areas orwebbing at strut junction points. A light microscope image was used torecord lack of obvious deformity in the stent structure. Coating imageswere assessed on multiple points over the outer and inner surfaces ofthe struts, at low (45×) and high (5000× and 20,000×) magnifications.For production lots, samples were selected randomly from each lot.

Surface coating thickness uniformity was also assessed by SEM imaging ofcross sections of tangential cuts made by glass blade microtome at twoor more points on each individual stent. Because the nanocompositecoating distorted under conditions of room-temperature sectioning,tangential cryomicrotomy was used to cut the coating on the selectedstrut at low temperature. A series of experiments were done to find theoptimal temperature. At −120° C., the coating started coming off aspieces, leaving the cutting edge clean. Because of the low stiffness ofthe coating, a glass knife was used to cut at 1 mm/s cutting rate and0.5 um per step feeding rate. SEM images were then taken and thethickness for each type of coating was estimated.

Coating thickness was also assessed using profilometry. Because theprofile across the curved stent surface could not be obtained, coatingswere sprayed on 1-cm-square polished 316L stainless steel plates, usingsimilar spray conditions and time for each of the polymer-drug blendsand surface types, respectively. Three squares were placed on a flatfixture and coated during a single spray period. Samples were evaluatedusing a Dektak 3030 profilometer (Veeco Instruments, Woodbury, N.Y.,USA) and a Tencor P-10 profilometer (KLA-Tencor Instruments, San Jose,Calif., USA). As the stylus scanned the surface, the profile wasrecorded. The stylus load was kept at 0.05 mg so that the coating wouldremain intact without leading to false measurement. Thickness data wasderived from the profile.

Imaging

Imaging experiments utilized light images of stents taken using a NikonModel SMZ1500 stereomicroscope. Higher-magnification surface images weretaken using a Hitachi Model S-3500N VP scanning electron microscope(SEM). For this, samples were mounted and then coated with gold under250 μm Hg of argon, using 15 μA of current for 1.5 minutes, and thenplaced on the microscope stage. For atomic force microscopy, a DigitalInstruments Nanoscope III MultiMode Scanning Probe Microscope with anauxiliary Extender electronics module was used in tapping mode. ForFourier Transform Infrared (FTIR) Spectra microscopy, PLCL coated stentswith and without dexamethasone were imaged using a Nicolet Magna-IR 750model attached to a Nic-Plan IR Microscope. The microspectroscopy wasdone under reflectance mode with 10 μm beam size. The background wascollected on a mirror with gold coating. FTIR spectra on multiple spotsof the coating were compared.

Coating Adherence

Two techniques were used. Coating adherence after balloon expansion ofthe stent was assessed by SEM imaging, looking for patterns of obviouscracking or delamination of the coating surface from the stentstructure. In another approach, we also explored use of a “tape test,”in which the coated stent mounted on a rigid wire fixture was placedwith gentle pressure onto the adhesive side of Scotch Magic tape (3M,St. Paul, Minn., USA) and then removed from the tape quickly by pullingat either end of the wire fixture. This method was less satisfactory dueto problems standardizing the technique and deforming the stent.

Effect of Humidity on Coating Surface

Because the PLCL polymer is known to biodegrade in the presence ofwater, we evaluated the effect of short-term exposure of a high moistureenvironment on the surface characteristics. Stents coated with the PLCLopen matrix coating and the PLCL smooth coating (i.e., closed filmcoating) were exposed to 99% relative humidity at room temperature in aclosed container. Stents were evaluated at 24 and 72 h and these imagescompared to control stents that were maintained under dry conditions.

Statistical Methods

Experimental outcome data descriptive statistics were calculated usingMicrosoft Excel and reported as mean, standard deviation (SD) andcoefficient of variation (CV).

RESULTS OF EXAMPLES Design of Experiment (DOE) Results: Evaluation ofthe Spray Process Variables on Coating Matrix

These experiments were conducted to investigate the impact of PLCLpolymer concentration in final spray stream, presence of the drugdexamethasone (DEX), conductivity, and distance from spray head totarget on the final coating matrix appearance. The desired coatingmatrix was a uniform open matrix of round particles. As explained above,a Design of Experiment (DOE) approach was taken to setting up theexperimental conditions and evaluating the impact of the various processparameters. This is a highly efficient way of identifying optimalcoating conditions for a particular polymer and coating finish. Theexperimental conditions are summarized in the table of FIG. 9 and theimages of the resulting coatings shown in FIG. 10. The table of FIG. 9includes the experimental conditions and outcome measures to assessimpact of process parameters on achieving desired coating surfaceappearance.

The effect of the process parameters with respect to achieving thedesired coating appearance is summarized in the table of FIG. 11 whichshows the relationship of process parameters to experimental outcomevariables (⇄ little effect, ↑ increase). As can be seen from this chart,a higher polymer-to-diluent ratio (i.e., liquid spray compositionprovided at the inner opening or inner capillary to liquid diluentcomposition provided at the outer opening of the spray apparatus), isthe sole factor associated with greater coating weight; spray distance(i.e., distance from dispensing end to the target) and conductivity ofthe diluent in the outer capillary (which has a major impact onconductivity of final spray stream) are both associated with therequirement for a higher spray voltage, and a higher conductivity is thesole factor associated with achieving the desired coating surface.

Another factor that was determined to affect the stability of the sprayoperation was defining the range of voltage for a particular fluid thatwas associated with a stable cone-jet mode. The cone-jet mode is theoperating mode that produces the most uniform particles. The voltagethat must be applied to achieve the cone-jet mode is related to theconductivity of the spray fluid, so in one sense it is an outcomemeasure defined by the feed fluid. However, it can also be controlledwithin a certain range to produce the cone-jet operation. As shown inFIGS. 2A-2C herein, voltage is increased, the dripping spray tip (FIG.2A) first assumes a pulsating appearance (FIG. 2B) and eventually thecone-jet mode (FIG. 2C) which produces the most stable nanometer-sizedparticles.

As has been reported previously by Chen and Pui (1995), there ishysteresis in the operating current across the target during cone-jetoperation and the operating voltage, which is different when the voltageis increasing than when it is decreasing. This is a unique relationshipfor each polymer/solvent combination, as shown in FIG. 12. In thisexperiment, the polymer was PLCL and the solvent was acetone alone or ablend of acetone and chloroform (90:10) (used to produce the open matrixand smooth coating (i.e., closed film) surfaces, respectively). FIG. 12shows the hysteresis effect on the relationship between voltage andcurrent through the spray target while operating electrospray in thecone-jet mode. Cone-jet (CJ) operation was observed within the voltageranges that were marked by rapid changes in the current, depending onwhether voltage was increasing or decreasing.

These process control experiments are significant because theydemonstrate that a set of operating parameters can be identified for agiven polymer, drug and solvent combination that produce a desiredsurface finish (e.g., selection of a particular type of coating). TheDesign of Experiment (DOE) methodology provides a powerful tool foridentifying these parameters. This systematic approach provides afoundation for scale-up in manufacturing and designing automated processcontrol features.

Results of Coating Weight Consistency for Production Lots of ThreeDifferent Coating Surfaces

Three separate lots of a minimum of 10 stents each were coated with twodifferent polymers, both containing the anti-inflammatory agentdexamethasone. The biodegradable polymer PLCL was used to apply coatingswith two unique surface characteristics—a highly porous (“open matrix”)finish, or a smooth (“closed”) finish. The drug-eluting polymerChronaflex AR produced a smooth, “closed” finish with the family ofsolvents investigated. Coating spray times were approximately 20 minutesfor each of these spray runs. Images for each of these coating surfacesare provided under description related to “Coating Adherence,” below.Stent and coating weights are summarized in the table of FIG. 13 whichshows stent and coating weights for each lot of the various coatingpolymers and surfaces.

Coating weights of individual stents were plotted for each lot todetermine how many individual samples had coating weights exceeding 2SD. FIG. 14 shows a plot for the open-matrix coating with PLCL, FIG. 15for the smooth coating (i.e., closed film) with PLCL, and FIG. 16 forthe smooth coating with Chronoflex AR. Notably, in none of the lots dida single stent coating weight exceed 2 standard deviations.

FIG. 14 shows the coating net weights for a lot of stents produced withthe open matrix PLCL coating. The optimum solvent for PLCL was acetone.To produce this coating finish, the ideal feed rate of thepolymer/acetone solution was determined to be 6.5 μl/min sprayed at adistance of 10 mm. (See, for example, DOE results for the impact ofvarious spray operating parameters on final coating appearance.)Maintenance of the cone-jet mode required some increase of voltageduring each individual spray run. For the stents in this lot, the innercapillary feed was PLCL 5% and DXM 0.5% in acetone at a rate of 1.5μl/min, with an outer capillary feed of acetone, with nitric acid addedto adjust conductivity to 6.8 μS/cm, at a flow rate of 5 μl/min.

FIG. 15 shows coating net weights for a lot of stents produced with thesmooth PLCL coating (i.e., closed film coating). To produce this coatingfinish, the feed rate of the polymer/acetone/chloroform solution was10.75 μl/min sprayed at a distance of 10 mm. Voltage was stablethroughout each individual spray run. For the stents in this lot, theinner capillary feed was PLCL5% and DXM 0.5% in acetone at a rate of0.75 μl/min, with an outer capillary feed of acetone 40% and chloroform60%, at a flow rate of 10 μl/min.

FIG. 16 shows coating net weights for a lot of stents produced with thesmooth Chronoflex AR coating (i.e., closed film coating). The optimumsolvent for this polyurethane was a blend of tetrahydrofuran and methylalcohol. Polymer solution feed rate was 10.0 μl/min sprayed at adistance of 8 mm. Voltage was stable throughout the coating of eachindividual stent. For the stents in this lot, the inner capillary feedwas CFR 2% and DXM 0.2% in THF 83.3% and methanol 16.7% 2.0 μl/min, withan outer capillary feed of THF 83.3% and methanol 16.7% at a flow rateof 8 μl/min.

The consistency of these coating runs is significant because itdemonstrates that these three different coatings can be reproduced withminimal between-stent variation in coating weight. These experimentsfurthermore demonstrate that coatings of acceptable weights can beachieved with these particular drug/polymer combinations.

One process parameter is the length of spray time. The coatings in theseexperiments, made using single spray units, took a spray time of 20-25min. This can be shortened by operating multiple spray units in serialor parallel or by adding additional spray heads targeting eachindividual stent.

Coating Transfer Efficiency Results

Coating transfer efficiency is the amount of sprayed material that isapplied to the stent surface. Transfer efficiency for each of the threecoatings is shown in the table of FIG. 17 which shows coating transferefficiency as a function of coating polymer, surface and solvents. Thelowest transfer efficiency was seen for the PLCL open matrix finish. Thespray pattern for this finish was much broader than seen for the othertwo finishes due to the higher conductivity of the sprayed material.Higher conductivity fluids generate smaller nanoparticles, which appearsto correlate with wider spray patterns. A broader spray pattern meansthat more material is applied beyond the stent target area to thefixture.

Coating Thickness Results

Coating thickness was assessed by two different methodologies:profilometry, which uses a surface scan on the coating and a baselineuncoated reference area, and cyromicrotomy followed by SEM imaging.

Profilometry was only capable of measuring thickness on flat surfaces.Samples were prepared by coating the surface of the polished 316stainless steel squares described earlier. While coating thicknessestimates were roughly equivalent to those reported above forcryomicrotomy, this method is of limited utility because it is notapplicable in its present form for the curved surface of the coronarystent. An example of a scan is shown for a PLCL open matrix coating onthe flat surface in FIG. 18 which is a profilometer scan made with aTencor P10 instrument. Coating thickness was estimated at approximately10 μm. It may be possible that profilometry could be modified for use onstents.

Cryomicrotomy followed by SEM imaging was of considerably greaterutility. The cross-sectional images also provide a view of theuniformity of the coating. Examples of microtomed samples are shown inFIGS. 19 a-c. FIG. 19 shows cross-sectional images of the three coatingtypes produced during the production lots. Extraneous material in eachimage is debris caused when the microtome glass knife shatters thesurface during section cuts. FIG. 19 a shows an open matrix PLCLcoating. The crystalline-appearing debris is fragments broken from theglass knife when it hits the stent surface. Coating thickness ismeasured to be 13.48 μm. FIG. 19 b shows a smooth PLCL closed filmcoating. Thickness is measured to be 11.44 μm. The minor separationbetween the coating and the stent surface that is visible in this imagemay be artifact produced when the coated stent is cooled under liquidnitrogen in preparation for sectioning. FIG. 19 c shows a Chronoflex ARcoating. Thickness is measured to be 3.13 μm.

Cryomicrotomy and SEM imaging is the most practical method for assessingcoating thickness. Ideally a profilometer-type assay could be developed,using cryomicrotomy/SEM imaging as a benchmark for method validation.

Results for Coating Surface Characteristics, Surface Uniformity andAdherence, Before and After Balloon Expansion

Coating surface characteristics were initially evaluated through pilotstudies and SEM imaging. After optimizing process variables for aparticular polymer/drug combination and the desired surfacearchitecture, we needed to demonstrate that these surfacecharacteristics could be reliably and consistently produced. Using theuniform lots of coated stents, the consistency of coating surfacecharacteristics was assessed by randomly selecting and SEM-imaging threestents from each lot in the non-expanded state and three stents afterballoon expansion to 3 mm. Representative images for each coating (asshown by the key to the images provided in the table of FIG. 21) areshown in Figures a-f. Small type information too small to read at thebottom of each image is summarized in the key.

As is clear in the images of FIG. 20 a-f, all three types of coatingsurfaces are uniform without obvious coating voids. Coatings were deemedto be acceptable if they exhibited overall uniformity, no obviouscoating voids, evenness on the internal surface of the strut, and lackof webbing or pooling and strut angles.

We also conducted pilot spraying experiments using PIB 1% in THF, andPTHFMA-EA 2% in THF, both with dexamethasone at 10% the level of thepolymer. The PIB gave a smooth coating, while the PTHFMA-EA gave alarge, irregular open matrix surface.

In the images shown in FIGS. 20 a-f, all surfaces appeared to beadherent prior to balloon expansion. The PLCL open matrix coating showedevidence of minor cracking along strut angles after balloon expansion.At higher magnification (not shown), these cracks did not appear toreach the stent surface. None of the coatings delaminated after balloonexpansion. We also evaluated adherence using the “Scotch Tape” test. Inpractice, this test was difficult to standardize. While this removedsome of the material from the open matrix PLCL coating (image notshown), some particulate surface remained. This finding is consistentwith the balloon expansion observation.

These images demonstrate that all three polymer/drug coatings could beuniformly applied. We were only able to produce the open matrix surfacewith PLCL, but this was very uniform. Both PLCL and Chronoflex AR gavevery smooth coatings with minor surface variations only visible at20,000× magnification. Inner and outer strut surfaces were similar inappearance and there were no obvious voids, demonstrating the importantsheath-like coating that is achieved with the non-line-of-sightelectrospray process.

The polymers listed in the examples that have been sprayed provide astrong foundation for extending the coating capabilities to othersystems and/or for use on other medical devices or objects and also fordeveloping routine SEM imaging as a key quality control assessment toolfor scaled-up manufacturing.

Methods for testing coating adherence under likely stress conditions,include, for example, balloon expansion. Adherence could be improved forsome polymers, if necessary, with use of a surface priming treatment onthe stent surface. The open matrix PLCL coating showed minor cracking atthe strut points after balloon expansion, providing information forfurther coating optimization.

Matrix Uniformity Results

In addition to SEM imaging, we undertook a limited evaluation of matrixuniformity with scanning probe microscopy (SPM) in tapping mode. Due tothe technical difficulties in working with a curved surface, coated flatstainless steel squares were used as the sample. The response to thesurface of the PLCL open matrix sample was overwhelmed by opentopography. The response to the surface of the PLCL flat surface did notdetect any differences in response over the area evaluated. Becausedexamethasone is soluble in the solvents used to apply the PLCL, it ispossible that the drug remained in an amorphous state uniformlydistributed throughout the polymer.

We also explored using FTIR microscopy to evaluate chemical uniformityin the matrix. FTIR spectra on two spots of the coating were comparedfor stents coated with PLCL alone and in combination with dexamethasone.Spectra for PLCL alone and PLCL plus dexamethasone are shownsuperimposed in FIG. 22. The peaks at 1620 and 1600 cm⁻¹ represent thevibrational mode of A-ring and C═C stretch respectively and the peak at1660 cm⁻¹ represents the C₃ carbonyl stretch of dexamethasone. Thosethree peaks are not present in the coating made without dexamethasone.The intensities of those peaks observed at different locations of thestent coated with PLCL plus dexamethasone (data not shown) were similar,suggesting that the dexamethasone (DXM) was also distributed uniformly.

Uniform distribution of drug throughout the coating matrix is requiredto ensure even delivery to the coronary vessel wall. SPM was not capableof discerning matrix differences with the polymer/drug combinations usedin these experiments. While FTIR microscopy can detect the presence ofdrug at selected site it does not appear to be sensitive enough toprovide quantitative information.

Matrix Stability with Humidity Results

When stents coated with the PLCL polymer and dexamethasone were exposedto a 99% relative humidity (RH) environment at room temperature, changesin the surface morphology were seen for both the smooth coating and theopen-matrix coating, shown in FIGS. 23 a-b. With the open-matrix coatingof FIG. 23 a, the round particles present in the control stents were nolonger distinct by 24 hours and appeared to have become contiguous byeither swelling or melting. With the smooth coating of FIG. 23 b,surface irregularities not present on the control stents appeared asearly as 24 hours.

While the PLCL biodegradable polymer provides considerable flexibilityin engineering both smooth and particulate surface features, it is verysensitive to environmental moisture. This surface could be a way ofsupplying a rapid burst of drug release due to the high surface areathat is exposed to the points of contact in the vessel.

OTHER APPLIED COATING EXAMPLES USING LIQUID SPRAY AND DILUENTCOMPOSITIONS

Using the same electrospray setup described above, various solutionswere sprayed to form coatings on objects as shown below. Liquid spraycompositions (e.g., solids and solvents) were provided as the inner flow(IF) to the inner opening of the dual concentric opening nozzlestructure (i.e., inner capillary) and liquid diluent compositions wereprovided as the outer flow (OF) to the outer opening of the dualconcentric opening nozzle structure as indicated in the tablesassociated with each example. In each example, images are matched to thetable by the Sample #.

Example 1

The solution samples listed in the table of FIG. 24A were sprayed underthe conditions provided therein. FIG. 24B shows images of the coatingsresulting from the spraying of the samples in cone-jet mode. The imagesfor each solution are provided in higher and lesser magnification. Thesolution (0.9% poly(styrene-b-isobutylene-b-styrene (abbreviatedSIBS)+0.1% paclitaxel (PTx) in 85% tetrahydrofuran (THF) and 14%methanol (MEOH) could be sprayed as open matrix coating. In order toobtain a closed film (smoother) coating, toluene was added into themixture.

Example 2

The solution samples listed in the table of FIG. 25A were sprayed underthe conditions provided therein. FIG. 25B shows images of the coatingsresulting from the spraying of the samples in cone-jet mode. The imagesfor each solution are provided in higher and lesser magnification. Thesolution (0.9% SIBS+0.1% PTx in 99% THF) didn't spray in cone-jet modeinitially because of the low conductivity. More volatile and conductivesolvent such as methanol was used in outer nozzle so that theopen-matrix coating was achieved. Then, the closed film coating wasobtained by adding the outer flow and changing the ratio between theinner and outer flow.

Example 3

The solution sample listed in the table of FIG. 26A was sprayed underthe conditions provided therein. FIG. 26B shows images of the coatingresulting from the spraying of the samples in cone-jet mode. The imagesfor each solution are provided in higher and lesser magnification. Thesolution (2.25% SIBS+0.25% PTx in 97.5% THF) has high viscosity, whichprevented it from being sprayed at cone-jet mode. Solvent blend wasintroduced into outer nozzle so that the closed film coating wasachieved.

Example 4

The solution samples listed in the table of FIG. 27A were sprayed underthe conditions provided therein. FIG. 27B shows images of the coatingsresulting from the spraying of the samples in cone-jet mode. The imagesfor each solution are provided in higher and lesser magnification. Thesolution (4.5% SIBS+0.5% PTx in 95% THF) has high viscosity, whichprevents it from being sprayed at cone-jet mode. Solvent blend wasintroduced into outer nozzle so that the open-matrix and the closed filmcoatings were achieved.

Example 5

The solution samples listed in the table of FIG. 28A were sprayed underthe conditions provided therein. FIG. 28B shows images of the coatingsresulting from the spraying of the samples in cone-jet mode. The imagesfor each solution are provided in higher and lesser magnification. Anopen matrix coating could be easily achieved with this solution (4.5%PLCL+0.5% DEX in 95% Acetone) because of the low boiling point andhigher conductivity of acetone. In order to have a closed film coating,the acetone and chloroform. blend was used as outer solvent.

Example 6

The solution samples listed in the table of FIG. 29A were sprayed underthe conditions provided therein. FIG. 29B shows images of the coatingsresulting from the spraying of the samples in cone jet mode. The imagesfor each solution are provided in higher and lesser magnification. Openmatrix coating could be easily achieved with this solution (5% PLCL in95% Acetone) because of the low boiling point and higher conductivity ofacetone. In order to have closed film coating, the acetone andchloroform blend was used as outer solvent.

Example 7

The solution sample listed in the table of FIG. 30A was sprayed underthe conditions provided therein. FIG. 29B shows images of the coatingresulting from the spraying of the sample in cone-jet mode. The imagefor the solution was provided in higher and lesser magnification. Thesolution (1.8% PLCL+0.2% DEX in 82% THF and 16% MEOH) didn't spray atcone-jet mode initially. A small amount of methanol was added into outernozzle to provide some conductivity. A closed film coating was achievedby this way.

Example 8

The solution sample listed in the table of FIG. 31 was sprayed under theconditions provided therein. FIG. 32 shows images of the coatingresulting from the spraying of the sample in cone-jet mode. The imagesfor the solution are provided in higher and lesser magnification. MEKhas a boiling point of 79-80.5 C., but the conductivity is lower thanmethanol, which was the reason why this solution (0.9% SIBS+0.1% PTx in69.7% THF and 29.3% MEK) didn't spray at cone-jet mode initially. Asolvent blend of methanol and THF was added into outer nozzle to providemore conductivity. An open matrix coating was achieved by this way.

Example 9

The solution sample (2% DEX in 40% ethanol (ETOH) and 60% ACETONE)listed in the table of FIG. 33 was sprayed under the conditions providedtherein. FIG. 34 shows images of the coating resulting from the sprayingof the sample in cone-jet mode. The images for the solution are providedin higher and lesser magnification. Unlike the other example 1-10, thissolution sample was sprayed using a triple concentric opening nozzle,like that described with reference to FIG. 7B. The triple nozzle wasused to encapsulate the drug with the PLCL. Acetone was used at theoutermost nozzle.

The apparatus used to spray the coating was equivalent to that shown inand described with reference to FIG. 7A modified with the dual capillarytube distributor head 400 shown in and described with reference to FIG.7B. The apparatus used was configured with a center capillary tube 413having an outer diameter of about 558.8 μm (0.022 inches) and an innerdiameter of about 304.8 μm (0.012 inches). The second capillary tube 414concentric with the center capillary tube had an outer diameter of about1041.4 μm (0.041 inches) and an inner diameter of about 685.8 μm (0.027inches). The distance d1 shown in FIG. 7B from the end of taperedsection 335 to the end of the metal casing 322 is about 1143 μm (0.045inches). The diameter d2 of the first end 336 of the nozzle portion ormetal casing 322 is about 6426 μm (0.253 inches). The outer diameter d4of the second end 338 of the nozzle portion 322 is about 1549 μm (0.061inches) and an inner diameter d3 of about 889 μm (0.035 inches). Thedistance d5 from the tip of the second end 338 of the nozzle portion 322to the tip of the end of the second capillary tube 414 is about 508 μm(0.020 inches). The gap d6 at the tip of the second capillary tube 414is about 685.8 μm (0.027 inches).

The dispensing device was constructed of various materials. Primarily,the conductive elements were constructed of stainless steel, theapparatus was used in a chamber made of plexiglass, and insulative partsthereof were made of a plastic, black delrin, material. A voltage of4300 volts was applied to conductive element 312. The distance from thedispensing tip 495 of the second capillary tube 414 to the target wasabout 8 mm.

The inner capillary flow rate was 0.75 μl/min and the stream contained2% dexamethasone in a 2:3 blend of acetone and ethanol. The secondcapillary flow rate was 1.5 μl/min and the stream was 5% PLCL inacetone. The third and outer nozzle flow rate was 5 μl/min and containedacetone only.

Discussion Regarding Results

The electrospray coating system and process proved very flexible. Thesystem was able to apply a range of polymers of differing performancequalities and solvent requirements. For each condition studied, a set ofoperating parameters was successfully identified that provided a conejet spray throughout the coating as well as the desired surfacearchitecture. The system proved to be reliable and flexible enough toaccommodate solvents over a range of polarities and conductivities.

A key element to the successful spray operation was the ability to mergesolvent streams at the spray tip (e.g., a lower conductivity liquidspray composition including a polymer, drug and suitable solvent with ahigher conductivity liquid diluent composition such as one that includesan addition of nitric acid). This feature of the spray nozzle design haspermitted us to spray both polar solvents and non-polar solvents ofextremely low conductivity.

Important objectives related to scale-up for manufacturing wereidentified. The system produced even coatings on all intricate surfacesof a stent without webbing or coating voids. Coating weights wereuniform within a tight range during lot production. Reproduciblecoatings were produced with different surface characteristics, includingthe preservation of particle architecture. The strikingly differentcoating types achieved with PLCL polymer, just by altering the sprayoperating parameters, were noteworthy. The open-matrix coating has amuch greater surface area and would be presumed to alter drug releasecharacteristics.

This open matrix coating with its preserved nanoparticulatearchitecture, which we have now been able to replicate with two polymershaving very different solvent requirements, is desirable, includingpotential variations that combine more than one active ingredientapplied jointly or individually to create unique pharmacokinetics.

In view of the experiments, various modifications for the sprayapparatus may be made to so as to include monitoring and controlling theprocess in view thereof with respect to any of the following: surfacedust and fibers that contaminated the spray surface; imprecise controlson gas flow and composition through the spray chamber; inadequateevaporation rates of solvents; temperature fluctuations in ambient air;humidity fluctuations in ambient air; the need to eliminate gas bubblesfrom the spray feed material; the need to adjust the voltage of thepower supply manually; need of bright lighting for video imaging andimpact of ultraviolet light on cure of certain polymers; overspray ofpolymer and potentially toxic drug material and inability to clean allsurfaces of the spray chamber without dismantling it; and build-up ofcoating overspray on the fixture leading to changes in the voltagesettings required to operate in cone jet mode.

For example such modification may include additional mechanisms toprovide management of air or gas stream quality flow through improvedfiltration, temperature and moisture control, as well as flow ratecontrols. Improved control features will also enable operators to modifyor facilitate solvent evaporation by improved temperature and gascontrol.

Yet further, automation of voltage control may be used. For example,such automation may include video imaging assessment of the cone-jet(s)during operation and, where indicated, feedback adjustments and/orimmediate termination of spray operations. For example, if the cone jetbecomes unstable and begins to “spit,” this can result in discharge ofexcessive solvent and cause blemishes on the coated surface. The “spit”can be seen visually and the effects reduced by stopping the spray ormasking the spray surface, but there is often insufficient time toreact. It should be possible through image monitoring and analysis tolimit or prevent the impact on the spray surface and make needed processcontrol modifications.

Yet further, improved light sources may be used, with the possibility oflimiting certain wavelengths, and three-dimensional video camerapositioning for better imaging of both the target and cone-jet may beused. Further, placing a moving stage and/or spray head parts outside ofthe actual spray chamber may be used to improve cleanability and theability to contain more toxic spray elements during spray operations.

Still further, material containment and safe handling as well astreatment of the vented air or other gases passing through the spraychamber may be used to remove any stray particles.

References cited in the Examples above include:

-   1. Alexis F, Venkatraman S S, Rath S K, Boe F. In vitro study of    release mechanisms of paclitaxel and rapamycin from    drug-incorporated biodegradable stent matrices. J Controlled Release    98:67-74 (2004).-   2. Chen D-R, Pui D Y H, Kau nan S L. Electrospraying of Conducting    Liquids for Monodisperse Aerosol Generation in the 4 nm to 1.8 m    Diameter Range, J Aerosol Sci, 26(6) 963-977 (1995).-   3. Puskas J E, Chen Y, Dahman Y, Padavan D. Polyisobutylene-Based    Biomaterials. Feature Article. J. Polym. Sci., Chem.,    42(13):3091-3109 (2004).-   4. Ranade S V, Miller K M, Richard R E, Chan A K, Allen M J, Helmus    M N. Physical characterization of controlled release of paclitaxel    from the TAXUS™ Express²™ drug-eluting stent. J Biomed Mater Res    71A:625-634 (2004).-   5. Szycher M, Armini A, Bajgar C, Lucas A. Drug-eluting stents to    prevent coronary restenosis.    (www.implantsciences.com/pdf/IMXpaperv2-rev2.pdf) (2002)-   6. Verhoeven M L P M, Driessen, A A G, Paul A J, Brown A, Canry J-C,    Hendriks M. DSIMS characterization of a drug-containing    polymer-coated cardiovascular stent. J Controlled Release 96,    113-121 (2004).

All patents, patent documents, and references cited herein areincorporated in their entirety as if each were incorporated separately.This invention has been described with reference to illustrativeembodiments and is not meant to be construed in a limiting sense. Asdescribed previously, one skilled in the art will recognize that othervarious illustrative applications may use the techniques as describedherein to take advantage of the beneficial characteristics of theparticles generated hereby. Various modifications of the illustrativeembodiments, as well as additional embodiments to the invention, will beapparent to persons skilled in the art upon reference to thisdescription.

1-42. (canceled)
 43. A method of coating at least a portion of anobject, the method comprising: providing an object in a defined volume,wherein the object comprises at least one surface; providing one or morenozzle structures, wherein each nozzle structure comprises one or moreopenings terminating at a dispensing end of each nozzle structure;providing one or more flows of liquid compositions to the openings;generating a plurality of charged coating particles forward of thedispensing end of each nozzle structure to apply a coating to the atleast one surface of the object, wherein generating the plurality ofcharged coating particles comprises dispensing a stream of a pluralityof microdroplets having an electrical charge associated therewith fromthe dispensing end of each nozzle structure by creating a cone jet fromthe one or more flows at the dispensing end of each nozzle using anonuniform electrical field between the dispensing end of each nozzlestructure and the object, wherein the plurality of charged coatingparticles having a nominal diameter of less than 10 micrometers areformed as the microdroplets evaporate, wherein using the nonuniformelectrical field between the dispensing end of each nozzle structure andthe object to generate the plurality of charged coating particlescomprises applying an electrical potential difference between thedispensing end of each nozzle structure and the object being coated soas to create the cone jet from the one or more flows at the dispensingend of each nozzle structure; and adjusting the electrical potentialdifference between the dispensing end of each nozzle structure and theobject being coated as the thickness of the coating increases so as tomaintain a stable cone jet at the dispensing end of each nozzlestructure.
 44. The method of claim 43, wherein the coating applied onthe at least one surface of the object is a uniform open matrix coating.45. The method of claim 43, wherein the coating applied on the at leastone surface of the object is a uniform closed film coating.
 46. Themethod of claim 43, wherein providing the one or more flows comprisesproviding a first flow of a liquid spray composition at an inner openingterminating at the dispensing end, wherein the liquid spray compositioncomprises at least a biologically active ingredient, a polymer, and asolvent suitable to at least partially dissolve the polymer, and furtherproviding a second flow of a liquid diluent composition at an outeropening terminating at the dispensing end concentric with the inneropening, wherein the liquid diluent composition has a high dielectricconstant.
 47. The method of claim 43, wherein adjusting the electricalpotential difference between the dispensing end of each nozzle structureand the object being coated further comprises: detecting at least onecharacteristic associated with the cone-jet; determining the stabilityof the cone jet based on the at least one characteristic; and adjustingone or more process parameters to maintain a stable cone-jet.
 48. Themethod of claim 47, wherein detecting at least one characteristicassociated with the cone jet comprises imaging the cone jet to determineat least one angle associated therewith.
 49. The method of claim 47,wherein detecting at least one characteristic associated with thecone-jet comprises detecting one or more flutters in the cone-jet. 50.The method of claim 47, wherein detecting at least one characteristicassociated with the cone jet comprises imaging the cone-jet to detectbubbles in at least one of the flows.
 51. The method of claim 43,wherein the plurality of coating particles have a nominal diameter ofgreater than about 1 nanometer and less than about 500 nanometers.
 52. Amethod of coating at least a portion of an object, the methodcomprising: providing an object in a defined volume, wherein the objectcomprises at least one surface; providing one or more nozzle structures,wherein each nozzle structure comprises one or more openings terminatingat a dispensing end of each nozzle structure; providing one or moreflows of liquid compositions to the openings; generating a plurality ofcharged coating particles forward of the dispensing end of each nozzlestructure to apply a coating to the at least one surface of the object,wherein generating the plurality of charged coating particles comprisesdispensing a stream of a plurality of microdroplets having an electricalcharge associated therewith from the dispensing end of each nozzlestructure by creating a cone jet from the one or more flows at thedispensing end of each nozzle structure using a nonuniform electricalfield between the dispensing end of each nozzle structure and theobject, wherein the plurality of charged coating particles having anominal diameter of less than 10 micrometers are fanned as themicrodroplets evaporate; detecting at least one characteristicassociated with the cone-jet; determining the stability of the cone jetbased on the at least one characteristic; and adjusting one or moreprocess parameters to maintain a stable cone-jet.
 53. The method ofclaim 52, wherein the coating applied on the at least one surface of theobject is a uniform open matrix coating.
 54. The method of claim 52,wherein the coating applied on the at least one surface of the object isa uniform closed film coating.
 55. The method of claim 52, whereinproviding the one or more flows comprises providing a first flow of aliquid spray composition to an inner opening terminating at thedispensing end, wherein the liquid spray composition comprises at leasta biologically active ingredient, a polymer, and a solvent suitable toat least partially dissolve the polymer, and further providing a secondflow of a liquid diluent composition to an outer opening terminating atthe dispensing end concentric with the inner opening, wherein the liquiddiluent composition has a high dielectric constant.
 56. The method ofclaim 52, wherein detecting at least one characteristic associated withthe cone-jet comprises imaging the cone jet to determine at least oneangle associated therewith.
 57. The method of claim 52, whereindetecting at least one characteristic associated with the cone jetcomprises detecting one or more flutters in the cone-jet.
 58. The methodof claim 52, wherein detecting at least one characteristic associatedwith the cone jet comprises imaging the cone jet to detect bubbles inthe one or more flows.
 59. The method of claim 52, wherein the pluralityof coating particles have a nominal diameter of greater than about 1nanometer and less than about 500 nanometers. 60-66. (canceled)
 67. Asystem for coating at least a portion of an object, the systemcomprising: at least one liquid composition source; a dispensing deviceconfigured to receive one or more flows of liquid composition from theat least one liquid composition source and dispense a plurality ofmicrodroplets having an electrical charge associated therewith from adispensing end of each of one or more nozzle structures into a definedvolume in which the object is placed; an electrode structure comprisingan electrode isolated from the dispensing ends of the one or more nozzlestructures, wherein the electrode structure is used to create anonuniform electrical field between the dispensing end of each nozzlestructure and the object to be coated, wherein the electrode structureis further used to create a cone jet from the one or more flows at thedispensing end of each nozzle structure when in operation to generate,the plurality of microdroplets; and detection and control apparatus toadjust the electrical potential difference between the dispensing end ofeach nozzle structure and the object being coated as the thickness ofthe coating increases so as to maintain a stable cone jet at thedispensing end of each nozzle structure during coating of the object.68. The system of claim 67, wherein the detection and control apparatusfurther is configured to detect at least one characteristic associatedwith the cone-jet, determine the stability of the cone jet based on theat least one characteristic, and adjust one or more process parametersto maintain a stable cone-jet.
 69. The system of claim 68, whereindetection and control apparatus comprises an imaging apparatus for usein determining at least one angle associated with the cone-jet.
 70. Thesystem of claim 68, wherein detection and control apparatus comprises animaging apparatus for use in detecting one or more flutters in thecone-jet.
 71. The system of claim 68, wherein detection and controlapparatus comprises an imaging apparatus for use in detecting bubbles inthe one or more flows.
 72. A system for coating at least a portion of anobject, the system comprising: at least one liquid composition source; adispensing device configured to receive one or more flows of liquidcomposition from the at least one liquid composition source and dispensea plurality of microdroplets having an electrical charge associatedtherewith from a dispensing end of each of one or more nozzle structuresinto a defined volume in which the object is placed; an electrodestructure comprising an electrode isolated from the dispensing ends ofthe one or more nozzle structures, wherein the electrode structure isused to create a nonuniform electrical field between the dispensing endof each nozzle structure and the object to be coated, wherein theelectrode structure is further used to create a cone jet from the one ormore flows at the dispensing end of each nozzle structure when inoperation to generate the plurality of microdroplets; and detection andcontrol apparatus to detect at least one characteristic associated withthe cone-jet, determine the stability of the cone-jet based on the atleast one characteristic, and adjust one or more process parameters tomaintain a stable cone-jet.
 73. The system of claim 72, whereindetection and control apparatus comprises an imaging apparatus for usein determining at least one angle associated with the cone-jet.
 74. Thesystem of claim 72, wherein detection and control apparatus comprises animaging apparatus for use in detecting one or more flutters in thecone-jet.
 75. The system of claim 72, wherein detection and controlapparatus comprises an imaging apparatus for use in detect bubbles inthe one or more flows. 76-80. (canceled)